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01 April 2016
EMA/272184/2016
Committee for Medicinal Products for Human Use (CHMP)
Assessment report
Uptravi
International non-proprietary name: selexipag
Procedure No. EMEA/H/C/003774/0000
Note
Assessment report as adopted by the CHMP with all information of a commercially confidential nature
deleted.
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Table of contents
1. Background information on the procedure ............................................ 6
1.1 Submission of the dossier ..................................................................................... 6
1.2 Steps taken for the assessment of the product .......................................................... 7
2. Scientific discussion .............................................................................. 8
2.1 Introduction ....................................................................................................... 8
2.2 Quality aspects ................................................................................................... 8
2.2.1 Introduction ..................................................................................................... 8
2.2.2 Active Substance .............................................................................................. 8
2.2.3 Finished Medicinal Product ............................................................................... 11
2.2.4 Discussion on chemical, pharmaceutical and biological aspects ............................. 13
2.2.5 Conclusions on the chemical, pharmaceutical and biological aspects .................... 13
2.2.6 Recommendation(s) for future quality development .............................................. 13
2.3 Non-clinical aspects ........................................................................................... 14
2.3.1 Introduction ................................................................................................... 14
2.3.2 Pharmacology ................................................................................................ 14
2.3.3 Pharmacokinetics ........................................................................................... 18
2.3.4 Toxicology ..................................................................................................... 21
2.3.5 Ecotoxicity/environmental risk assessment ........................................................ 29
2.3.6 Discussion on non-clinical aspects .................................................................... 29
2.3.7 Conclusion on non-clinical aspects .................................................................... 31
2.4 Clinical aspects ................................................................................................. 31
2.4.1 Introduction ................................................................................................... 31
2.4.2 Pharmacokinetics ........................................................................................... 32
2.4.3 Pharmacodynamics ......................................................................................... 38
2.4.4 Discussion on clinical pharmacology .................................................................. 40
2.4.5 Conclusions on clinical pharmacology ................................................................ 43
2.5 Clinical efficacy ................................................................................................. 44
2.5.1 Dose response studies .................................................................................... 44
2.5.2 Main study ..................................................................................................... 46
2.5.3 Discussion on clinical efficacy ........................................................................... 70
2.5.4 Conclusions on clinical efficacy ......................................................................... 74
2.6 Clinical safety ................................................................................................... 75
2.6.1 Discussion on clinical safety ............................................................................. 88
2.6.2 Conclusions on clinical safety ........................................................................... 90
2.7 Risk Management Plan ....................................................................................... 90
2.8 Pharmacovigilance ........................................................................................... 102
2.9 Product information ......................................................................................... 102
2.9.1 User consultation .......................................................................................... 102
2.9.2 Additional monitoring .................................................................................... 102
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List of abbreviations
6MWD 6-minute walk distance
6MWT 6-minute walk test
ADME Absorption, distribution, metabolism, excretion
AS Active substance
AUC Area under plasma concentration-time curve
AUCτ Area under plasma concentration-time curve during a dose interval
AUC0-∞ Area under plasma concentration-time curve from 0 to infinity
AUC0-t Area under plasma concentration-time curve from 0 to ‘t’ h
b.i.d. Twice a day
CAMPHOR Cambridge Pulmonary Hypertension Outcome Review
CEC Critical Event Committee
CES carboxylesterase
CFU Colony Forming Units
CHD congenital heart disease
CI Confidence interval
Cmax Maximum plasma concentration
Cmax,ss Maximum plasma concentration at steady-state
CTD Connective tissue disease
CTEPH Chronic thromboembolic pulmonary hypertension
Ctrough Plasma concentration at the end of one dose interval
Ctrough,ss Plasma concentration at the end of one dose interval at steady-state
Cu/C concentration of free (unbound) to total plasma concentration
CV Coefficient of variation
CVb Inter-subject coefficient of variation
CVw Intra-subject coefficient of variation
DMC Data Monitoring Committee (also referred to as DSMB, Data Safety Monitoring
Board)
DSMB Data Safety Monitoring Board
eGFR estimated glomerular filtration rate
EOS End of study
ERA Endothelin receptor antagonist
GC Gas Chromatography
GCP Good Clinical Practice
GLP good laboratory practice
GMP Good Manufacturing Practice
HCl Hydrochloric acid
HIV Human immunodeficiency virus
HPAH Heritable pulmonary arterial hypertension (formerly familial PAH)
HPLC(/DAD) High performance liquid chromatography (/Diode Array Detector)
ICH International Conference on Harmonisation
IMP Investigational medicinal product
IPAH Idiopathic pulmonary arterial hypertension
IPC In-process control
IP receptor Prostacyclin receptor, PGI2 receptor
IR Infrared
LC-MS/MS Liquid chromatography coupled to tandem mass spectrometry
LVEDP Left ventricular end diastolic pressure
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MACE Major adverse cardiovascular events
MAP Mean arterial pressure
mPAP Mean pulmonary arterial pressure
mRAP Mean right atrial pressure
NMR Nuclear Magnetic Resonance
NS304 selexipag
NT pro-BNP N-terminal pro-brain natriuretic peptide
NYAH New York Heart Association
PDE5 Phosphodiesterase type-5
Ph. Eur. European Pharmacopoeia
OL Open-label
PK Pharmacokinetic(s)
PD Pharmacodynamic(s)
RH Relative humidity
QC Quality control
SAD Single-ascending dose
SD Standard deviation
SE standard error
SRFI severe renal function impairment
t Time
t½ Terminal elimination half-life
tmax Time to reach maximum plasma concentration
tmax,ss Time to reach maximum plasma concentration at steady-state
UGT uridine-glucuronosyltransferase
USP United States Pharmacopoeia
UV Ultraviolet
WHO World Health Organization
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1. Background information on the procedure
1.1 Submission of the dossier
The applicant Actelion Registration Ltd. submitted on 1 December 2014 an application for Marketing
Authorisation to the European Medicines Agency (EMA) for Uptravi, through the centralised procedure
falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The eligibility to
the centralised procedure was agreed upon by the EMA/CHMP on 25 April 2013.
Uptravi, was designated as an orphan medicinal product EU/3/05/316 on 26 August 2005. Uptravi was
designated as an orphan medicinal product in the following indication: Treatment of pulmonary arterial
hypertension and chronic thromboembolic pulmonary hypertension.
Following the CHMP positive opinion at the time of the review of the orphan designation by the
Committee on Orphan Medicinal Products (COMP), this product was withdrawn from the Community
Register of designated orphan medicinal products on 17 February 2016 upon request of the sponsor.
The applicant applied for the following indication:
Uptravi is indicated for the long-term treatment of pulmonary arterial hypertension (PAH; WHO Group
I) in adult patients with WHO functional class (FC) II–IV. Uptravi is effective in combination with an
endothelin receptor antagonist (ERA) or a phosphodiesterase-5 (PDE-5) inhibitor, or in triple
combination with an ERA and a PDE-5 inhibitor, or as monotherapy.
Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated
with connective tissue disorders, and PAH associated with congenital heart disease with repaired
shunts (see section 5.1).
The legal basis for this application refers to:
Article 8.3 of Directive 2001/83/EC - complete and independent application. The applicant indicated
that selexipag was considered to be a new active substance.
The application submitted is composed of administrative information, complete quality data, non-
clinical and clinical data based on applicants’ own tests and studies and/or bibliographic literature
substituting/supporting certain test(s) or study(ies).
Information on Paediatric requirements
Pursuant to Article 7of Regulation (EC) No 1901/2006, the application included an EMA Decision(s) PIP
P/0154/2013 on the agreement of a paediatric investigation plan (PIP).
At the time of submission of the application, the PIP P/0154/2013 was not yet completed as some
measures were deferred.
Information relating to orphan market exclusivity
Similarity
Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No
847/2000, the applicant did submit a critical report addressing the possible similarity with authorised
orphan medicinal products.
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Applicant’s request(s) for consideration
New active Substance status
The applicant requested the active substance selexipag contained in the above medicinal product to be
considered as a new active substance in itself, as the applicant claims that it is not a constituent of a
product previously authorised within the Union.
Protocol Assistance
The applicant received Protocol Assistance from the CHMP on 24 February 2006 and 26 April 2007. The
Protocol Assistance pertained to non-clinical and clinical aspects of the dossier.
Licensing status
The product was not licensed in any country at the time of submission of the application.
1.2 Steps taken for the assessment of the product
The Rapporteur and Co-Rapporteur appointed by the CHMP were:
Rapporteur: Martina Weise Co-Rapporteur: Concepcion Prieto Yerro
• The application was received by the EMA on 1 December 2014.
• The procedure started on 24 December 2014.
• The Rapporteur's first Assessment Report was circulated to all CHMP members on 16 March 2015.
The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 25 March
2015.
• During the meeting on 23 April 2015, the CHMP agreed on the consolidated List of Questions to
be sent to the applicant.
• The applicant submitted the responses to the CHMP consolidated List of Questions on 23 July
2015.
• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List
of Questions to all CHMP members on 3 September 2015.
• During the CHMP meeting on 24 September 2015, the CHMP agreed on a list of outstanding
issues to be addressed in writing and oral explanation by the applicant.
• On the 29th of September, the Applicant requested an extension of the clock-stop of one month to
address the List of Outstanding Issues, which the CHMP agreed to.
• The applicant submitted the responses to the CHMP List of Outstanding Issues on 16 November
2015.
• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List
of Questions to all CHMP members on 4 and 14 December 2015.
• During the CHMP meeting on 17 December 2015 outstanding issues were addressed by the
applicant during an oral explanation before the CHMP. The CHMP agreed on a 2nd list of
outstanding issues to be addressed in writing.
• The applicant submitted the responses to the 2nd CHMP List of Outstanding Issues on 22
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December 2015.
• The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the 2nd
List of Questions to all CHMP members on 8 and 13 January 2016.
• During the meeting on 25-28 January 2016, the CHMP, in the light of the overall data submitted
and the scientific discussion within the Committee, issued a positive opinion for granting a
Marketing Authorisation to Uptravi.
• The CHMP adopted a report on similarity of Uptravi with Volibris, Opsumit and Adempas on 28
January 2016.
• Following a request from the European Commission dated 24 February 2016 to further motivate
its opinion dated 28 January 2016, in light of the overall data submitted by the applicant and the
scientific discussion within the Committee, the CHMP adopted on 1 April 2016 a revised positive
opinion for granting a Marketing Authorisation to Uptravi.
2. Scientific discussion
2.1 Introduction
2.2 Quality aspects
2.2.1 Introduction
Uptravi is presented as immediate release film-coated tablets containing 200 μg, 400 μg, 600 μg,
800 μg, 1000 mg, 1200 μg, 1400 μg and 1600 μg of selexipag as active substance.
Other ingredients in the tablet cores are mannitol (E421), maize starch, low substituted hydroxypropyl
cellulose, hydroxypropyl cellulose, and magnesium stearate. Ingredients in the film coating include:
hypromellose, propylene glycol, titanium dioxide, iron oxide yellow (E172), iron oxide red (E172), iron
oxide black (E172) and carnauba wax, as described in section 6.1 of the SmPC.
The finished product is available in polyamide / aluminium / high-density polyethylene / polyethylene
with an embedded desiccant agent / high-density polyethylene blister sealed with an aluminium foil
(Alu/Alu blister with desiccant), as described in section 6.5 of the SmPC.
2.2.2 Active Substance
General information
The chemical name of the active substance selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl)
amino] butoxy}-N-(methylsulfonyl) acetamide, corresponding to the molecular formula C26H32N4O4S
and has a relative molecular mass 496.62 g/mol. It has the following structure:
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Figure 1: Selexipag structure.
The structure of the active substance has been confirmed by elemental analysis IR, 1H- and 13C-NMR
spectroscopy, mass spectroscopy, UV spectroscopy and X-ray powder diffraction, all of which support
the chemical structure.
It appears as a pale yellow crystalline powder, non-hygroscopic powder. Selexipag shows different
solubility characteristics in aqueous solutions and is insoluble at pH 2 to 4, freely soluble at pH 8 and
very soluble from pH 9 to pH 12. Its dissociation constant pKa was found 2.6 when determined by UV
method. Its logP in 1-octanol/water was found to be 2.2, in 1-octanol/aqueous HCl pH 1.2 was found
3.0, and in 1-octanol/aqueous phosphate buffer, pH 6.9 was found 2.1.
Selexipag is achiral. Three crystal forms named Form I, II and III are identified and discussed. All
selexipag batches manufactured so far correspond to the polymorphic form I which is sufficiently stable
at room temperature. The amounts of Form II and III have been also monitored during stability
studies of the clinical batches and registration batches. For all batches, no change in the amount of
Form II and Form III can be observed for all conditions tested.
Selexipag is considered a new active substance from a quality perspective. The applicant compared its
structure with active substances within authorised products in the EU and demonstrated that it is not a
salt, ester, ether, isomer, mixtures of isomers, complex or derivative (e.g. pro-drug or metabolite) of
any of them.
Manufacture, characterisation and process controls
Selexipag is synthesized by a single manufacturer in four main steps using four well-defined starting
materials with acceptable specifications as shown in figure 1. Three intermediate products are
described. Critical steps have been defined and the in-process controls (IPCs) used to ensure the
process performs as expected are described. Satisfactory information on the molecular formulae,
weights, yield ranges, chemical structures of the starting materials, intermediates, reagents and
solvents, operating conditions such as temperatures, mixing times and the in-process controls was
provided. Any reprocessing, following ICH Q7 (crystallisation step or other appropriate chemical or
physical manipulation steps that are part of the established manufacturing process), will be preceded
by careful evaluation to ensure that the quality of the intermediate or active substance is not adversely
impacted. The manufacturing process was optimised to address an increase of an impurity and levels
of the undesired polymorphic form III.
The characterisation of the active substance and its impurities are in accordance with the EU guideline
on chemistry of new active substances. Potential and actual impurities were well discussed with
regards to their origin and characterised.
The active substance is packaged into two low-density anti-static polyethylene bags and closed with
resealable tie-wraps. The bags are placed into a high-density polyethylene drum closed with a lid. The
polyethylene bags comply with the relevant EC regulations and Ph. Eur. requirements.
Specification
The active substance specification includes appropriate tests and limits for: appearance and colour
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(visual inspection), clarity and colour of solution (Ph. Eur.), identity (IR, HPLC), residue on ignition/
sulfated ash (Ph. Eur.), heavy metals (Ph. Eur.), loss on drying (Ph. Eur.), assay (HPLC), related
substances (HPLC), residual solvents (GC), particle size (laser light diffraction) and microbiological
quality (Ph. Eur.).
Form II is exempted from routine control in the final active substance because it was never detected in
any batch manufactured and during stability studies. Two solvents are routinely tested since these
solvents are used in the final step of the manufacturing process. The proposed limit of ACT-333679 is
considered acceptable form a toxicological point of view because this is the active metabolite of
selexipag.
The analytical methods used have been adequately described and non-compendial methods
appropriately validated in accordance with the ICH guidelines. Satisfactory information regarding the
reference standard used for testing has been presented.
Batch analysis results from three registration batches and three validation batches all of commercial
scale were provided. The submitted batch analysis data comply with the specifications and confirm that
the manufacture is sufficiently robust and provide reassurance that the process yields active substance
of consistent quality. However, following the manufacturing process optimisation, only one batch has
been manufactured- the last validation batch. Therefore in order to demonstrate consistent quality the
active substance following the process optimisation the CHMP recommended to investigate first three
active substance batches (Continuous Process Verification Batches) intensively and the batch analysis
certificates and a Continuous Process Verification Summary Report for these batches should be
provided once the three batches have been manufactured i.e., presumably in 2019.
Stability
Stability data on three commercial scale and one supportive clinical batch of active substance in the
intended commercial packaging for up to 36 months (48 months for the clinical batch) under long term
conditions at 25 °C/60 % RH and for up to six months under accelerated conditions at 40 °C/75 % RH
according to the ICH guidelines were provided. The parameters tested were appearance, content of
polymorphic form III (not routinely performed), loss on drying, related substances, assay, microbial
limit (not routinely performed) and particle size distribution (not routinely performed). The same
analytical procedures as for the release analysis were used, which had been shown to be stability
indicating.
No significant changes or trends were observed either at long-term conditions or accelerated
conditions. The results comply with the current specifications. Similar results were obtained for the
supportive clinical batch and the registration batches. However none of the stability batches have been
manufactured using the optimised manufacturing process, therefore the CHMP recommended that
further stability data from the first three continuous Process Verification Batches to demonstrate
consistent quality of the active substance should be provided.
The stability of the active substance was also investigated one batch under stress conditions according
to the Notes for Guidance Q1A (R2) and ICH Q1B. Samples were exposed to heat and moisture, light
(solid state and solution), acidic, basic and oxidising conditions. Hydrolysis occurred under both acidic
and basic conditions. Degradation was also noted under oxidising conditions (hydrogen peroxide). Light
exposure of the substance in solution resulted in a significant increase of three impurities. In solid
state though, selexipag was shown to be not sensitive to light.
Based on presented stability data, the proposed retest period of 48 months below 25 °C is acceptable.
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2.2.3 Finished Medicinal Product
Description of the product and pharmaceutical development
Uptravi is an immediate release film-coated tablet. Tablets are debossed with a number indicating the
strength and also have different colours to allow strength differentiation.
Potential changes of the polymorphic form were investigated and the impact on the dissolution and
stability of selexipag film-coated tablets has been investigated too. Although process-induced phase
transitions might potentially occur to a certain extent, they would be below the limit where they would
have an impact on the properties of the finished product. In addition since no evidence for the
polymorphic change was detected in tablets stored for 18 months at 30°C/75% RH and additionally
stored for 1 week at 80°C and for 1 month at 60°C.
Once the compatibility of the active substance with different excipients was studied, further studies
were conducted which led to the selection of binder and disintegrant and diluents, and to the
optimisation of the composition. Some of them were subjected to photostability studies leading to the
conclusion that the core tablets were light-sensitive.
Due to the photo-sensitivity of the core tablets it was decided to apply a coating. After testing several
formulations with different combinations of these pigments the formulation to be used in clinical
batches was established.
Tablets of 100, 200, 400 and 800 µg were used in clinical trials. The strength of 200 µg was used in all
clinical trials, including the phase 3 pivotal study were only this strength was used to administer doses
up to 1600 µg. Tablets of 1600 µg were used in the in-vivo bioequivalence study intended to
demonstrate the equivalence of administering a single tablet of 1600 µg and 8 tablets of 200 µg. The
bioequivalence of the intermediate strengths is supported by in-vitro dissolution tests conducted at all
dose strengths in dissolution media with pH: 1.2, 4.5, 5.5 and 6.8. Since it is known that selexipag has
a low solubility especially in low pH aqueous buffer values, sink conditions for all strengths are
achieved at pH 6.8 only which is the pH of the dissolution medium used for routine QC testing. At pH
values where sink conditions may not be achievable for all strengths, in vitro dissolution may differ
between different strengths. For that reason, similarity of the dissolution profile has been
demonstrated at the same dose as per the guideline on the investigation of bioequivalence. As far as
the discriminatory power of the QC dissolution method this has been demonstrated with regard to
manufacturing and formulation changes.
The composition of core tablets used during the clinical trials was always the same proposed for
marketing authorisation and used to manufacture the 'registration batches' manufactured at
commercial scale for the validation of the manufacturing process and for the formal stability studies.
The exact colour of each tablet strength has been modified during development as it became apparent
that more strengths are needed in the clinic, however the coatings used contained the same qualitative
and quantitative composition in non-colouring components (hypromellose and propyleneglycol) and
differing only in the amounts of the same four pigments tested during development (titanium dioxide
and iron oxides red,yellow and black). These changes in the quantitative composition of the coloring
agents are not considered to affect either the performance characteristics of the tablets (e.g.,
dissolution rate) or the stability behavior.
Development batches during pharmaceutical and clinical development were manufactured in different
sites but from the optimisation studies onwards all batches (e.g. registration and stability) have been
manufactured at the proposed site.
The manufacturing process as such could be considered as standard considering the dosage form
(immediate release tablets) and the kind of operations used for manufacture. Nevertheless the very
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low load of active substance in the tablets (between 0.148 % and 1.185 % w/w of the core tablet)
poses a challenge to the manufacturing process. Considering this and the type of the dosage form it
was deemed reasonable that the critical quality attributes were the uniformity of the blends during the
manufacture, the content uniformity of the tablets (both coated and uncoated) and the comparison of
the dissolution behaviour of the tablets. In addition, degradation of the active substance (particularly
when stored under stress conditions) was detected and related to some extent with some
manufacturing parameters and has been addressed in the DoE optimization of the manufacturing
process.
Uptravi tablets are packed in Alu/Alu blister with embedded desiccant. The selected primary packaging
is common for this dosage form and the included desiccant has been shown to be protective against
degradation of active substance, in particular hydrolysis, as it has been confirmed in the stability
studies. The packaging material (including the desiccant) complies with the relevant EU regulations
and Ph.Eur. requirements.
Manufacture of the product and process controls
The product manufacture comprises the following main steps: dry blending, wet granulation, drying,
milling, lubrication, compression, coating, polishing and packaging. Due to the low drug load, the
process is considered to be a non-standard process. Critical steps have been identified and a number
of measures were implemented to mitigate the risk of content uniformity failure together with
adequate in-process controls for this type of manufacturing process and pharmaceutical form.
The manufacturing process has been validated at commercial scale with three batches of each strength
and one additional validation batch of each strength will be added before commercialisation. It has
been demonstrated that the manufacturing process is capable of producing the finished product of
intended quality in a reproducible manner.
Product specification
The finished product release and shelf life specification include tests and limits for: appearance, colour
and diameter (visual/calliper), average tablet mass (gravimetry), identification (HPLC/DAD), content
uniformity of dosage units (Ph. Eur.), water content (Ph. Eur), assay and content per tablet (HPLC),
impurities (HPLC), dissolution (Ph. Eur.- HPLC) and microbial quality (Ph. Eur).
The tests and acceptance criteria were set generally in accordance to ICH Q6A. For the actual limits set
for degradation products the results of clinical batches and stability data of registration batches and to
the thresholds established in the guideline ICH Q3(B) on impurities in new drug products were also
considered. In addition, mention is made to the fact that ACT-333679 is a know metabolite of
selexipag.
Considering that no evidence for the polymorphic change from Form I to Form II, or Form III was
detected in tablets during stability and stress studies, it is considered justified that a test for Forms II
and III not to be included in the finished product specification.
The analytical methods used have been adequately described and non-compendial methods
appropriately validated in accordance with the ICH guidelines. Satisfactory information regarding the
reference standard used for testing has been presented.
Batch analyses results of three commercial scale batches for each strength of Uptravi were provided
and all batches meet the specification.
Stability of the product
Initially only five strengths (i.e. 200, 400, 800, 1200 and 1600 µg) were considered for development
and stability studies were initiated with them. When it was decided to develop further intermediate
strengths (600, 1000 and 1400 µg) additional stability studies were initiated and, in addition, a
reduced testing approach applying bracketing /matrixing was applied. The design of stability studies is
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deemed satisfactory as it is according to the guidelines ICH Q1A on stability testing and ICH Q1D on
bracketing and matrixing designs. The justification for using a reduced testing scheme for intermediate
strengths is supported.
Stability data on three commercial scale batches per strength (for 200, 400, 800, 1200 and 1600 µg)
stored under long term conditions (25 ºC / 60% RH) and intermediate conditions 30 ºC / 75% RH for
up to 24 months and for up six months under accelerated conditions (40 ºC / 75% RH) were provided.
In addition stability data for three commercial scale batches per strength (for 600, 1000 and 1400 µg)
stored under long term conditions (25 ºC / 60% RH) and intermediate conditions 30 ºC / 75% RH for
up to 12 months and for up six months under accelerated conditions (40 ºC / 75% RH) according to
the ICH guidelines were also provided. All the stability batches are identical to those proposed for
marketing and were packed in the primary packaging proposed for marketing.
Samples were tested for appearance, colour, assay, degradation products, dissolution and microbial
quality. The analytical procedures used were the same as for release and were shown to be stability
indicating.
All results remain within shelf-life specifications for all the samples tested at all the sampling time
points under all storage conditions. No significant change was observed except for degradation
products. The levels of degradation products show a consistent increase under all storage conditions.
The increase is more relevant for the lower dose strengths and for higher temperature and relative
humidity. The applicant presented results of statistical analysis of stability data as per Appendix A of
guideline ICH Q1E to support the extrapolation of these conclusion to the remaining three strengths
(600, 1000 and 1400 µg). The statistical analysis is considered acceptable.
Photostability of selexipag 200, 400, 600, 800, 1000, 1200, 1400 and 1600 μg film-coated tablets has
been investigated in accordance with the ICH guideline Q1B. No significant difference in appearance,
color and assay could be observed between samples exposed to intense light and control samples. No
increase of known impurities was observed and no new impurities above the limits were observed.
Therefore Uptravi film-coated tablets can be considered as photo stable and it is not necessary to store
the product protected from light.
Based on the presented data, the proposed 3 year shelf life without any special storage conditions as
stated in the SmPC are acceptable.
2.2.4 Discussion on chemical, pharmaceutical and biological aspects
Information on development, manufacture and control of the active substance has been presented in a
satisfactory manner. The development, manufacture and controls of the finished product have been
sufficiently documented and justified. The results of tests of active substance and finished product
carried out indicate consistency and uniformity of important product quality characteristics, and these
in turn lead to the conclusion that the product should have a satisfactory and uniform performance in
clinical use.
2.2.5 Conclusions on the chemical, pharmaceutical and biological aspects
The quality of this product is considered to be acceptable when used in accordance with the conditions
defined in the SmPC. Physicochemical and biological aspects relevant to the uniform clinical
performance of the product have been investigated and are controlled in a satisfactory way.
2.2.6 Recommendations for future quality development
In the context of the obligation of the MAHs to take due account of technical and scientific progress,
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the CHMP recommends the following points for investigation:
1. The first three active substance batches should be investigated intensively and the
batch analysis certificates and a Continuous Process Verification Summary Report for
these batches should be provided once the three batches have been manufactured.
2. Further stability data from the first three continuous to demonstrate consistent quality
of the active substance should be provided.
2.3 Non-clinical aspects
2.3.1 Introduction
PAH is characterized by pulmonary vasoconstriction, vascular cell proliferation and vascular
hypertrophy leading to an increase in pulmonary artery pressure, right ventricular hypertrophy and
right heart failure (Stearman et al. 2014). Endothelial dysfunction plays a key role in the pathogenesis
of PAH and loss of expression of PGI2-synthase represents one of the phenotypic alterations present in
the pulmonary endothelial cells in severe PH (Tuder et al. 1999, Stearman et al. 2014). A decreased
expression of the IP receptor has been found in the remodeled pulmonary arterial smooth muscle.
The applicant provided non clinical data from a full non clinical programme as detailed below. The non
clinical studies performed with selexipag are summarized. In most original reports of the in-vitro
functional assays, the Applicant has given IC50/EC50 values for the total concentrations. In the
following the values for free IC50/EC50 values are also given, taking the extent of protein binding in the
incubation media into account.
2.3.2 Pharmacology
Selexipag is an orally active non-prostanoid prostacyclin (PGI2) receptor agonist with a long-half-life,
selectivity for the IP receptor minimizing off-target effects especially in the gastrointestinum and a lack
of IP receptor desensitization processes which avoids the development of tachyphylaxis. The active
metabolite ACT-333679 is at least 16-fold more potent than selexipag in cellular systems and is
present at 3- to 4-fold higher plasma concentrations than the parent drug at steady-state in humans.
The receptors sensitive to prostaglandins D2, E2, F2a, I2 and thromboxane A2 are termed the DP, EP,
FP, IP and TP receptors, respectively (Whittle et al. 2012, Yokohama et al. 2013).
Prostanoid receptors are classified into three groups according to molecular evolution, associated
primary G proteins and second messengers: cluster 1 consists of the relaxant EP2, EP4, IP and DP1,
which are coupled with Gsa proteins and therefore activate AC to increase cAMP; cluster 2 consists of
the contractile EP1, FP and TP, which couple with Gqa and increase intracellular calcium concentrations;
cluster 3 consists of the inhibitory receptor EP3, which is coupled with Gia and which can couple to both
elevation of intracellular calcium and a decrease in cAMP (review in Yokohama et al. 2013).
Prostacyclin (prostaglandin I2, PGI2), synthesized from arachidonic acid by the sequential action of
cyclooxygenase and PGI2 synthase in endothelial cells, is a potent vasodilator, antithrombotic and
antiplatelet agent. PGI2 plays a role in the development of pulmonary hypertension: in human
pulmonary hypertension, IP expression is decreased; overexpression of PGI2 synthase reduces
elevated pulmonary blood pressure, and IP knockout mice developed more severe pulmonary
hypertension and vascular remodelling after chronic hypoxic exposure (review in Smyth and Fitzgerald
2002).
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The human prostanoid IP receptor has been cloned and demonstrated to be a member of the G-
protein-coupled receptor gene superfamily (Boie et al. 1994). IP receptors are distributed widely
throughout the body with high expression in the lung, heart and kidney, and activation of IP receptors
is coupled to the formation of the second messenger cAMP (review in Smyth 2002). Prostanoids are
potent vasodilators and possess antithrombotic and antiproliferative properties; whereas the
pharmacological properties of prostanoids acting via the IP receptor are similar, they differ markedly in
pharmacokinetics (e.g. half-lives are 2 min for prostacyclin, but 30 - 80 min for treprostinil; review in
Olschewski et al. 2004). Several PGI2 analogues have been approved for the treatment of PAH,
including epoprostenol (intravenous), iloprost (inhaled), treprostinil (intravenous, subcutaneous and
inhaled (oral in US only)) and beraprost (oral in Japan and South Korea only). These PGI2 analogues
are non-selective IP receptor agonists, since they also activate other prostanoid receptors such as the
EP3 and EP4 receptors. The EP3 receptor is responsible for gastric contraction and vomiting induced by
PGI2 analogues (Morrison et al. 2010, Kan et al. 2002).
Primary pharmacodynamic studies
In-vitro:
Selexipag and its main metabolite ACT-333679 have high affinity to prostacyclin (PGI2) receptors
expressed in CHO cells with Ki values of 263 and 19.8 nM, respectively, and both substances show
selectivity for this receptor, since binding to 7 other prostanoid receptors (EP1-4, DP, FP and TP)
occurred at much higher (micromolar) concentrations (Kuwano et al. 2007). In contrast, PGI2
analogues (e.g. beraprost) have lower selectivity for PGI2 versus other prostanoid receptors.
Selexipag and its main metabolite ACT-333679 increased intracellular cAMP concentrations in CHO cells
expressing the human prostacyclin (PGI2) receptor with EC50 values of 177 and 11.5 nM, respectively,
and, therefore, metabolite ACT-333679 was about 16-fold more potent compared to selexipag in this
assay.
In HEK 293 cells expressing prostanoid receptors and using stimulation of adenylate cyclase as the
parameter, ACT-333679 and selexipag demonstrated pronounced species differences at the IP
receptor, whereas iloprost did not. The EC50 values for free substances at the human, rat and dog IP
receptors were 4, 170 and 1100 nM for selexipag, respectively, and 0.17, 3.1 and 14 nM for metabolite
ACT-333679, respectively, demonstrating sensitivity in the order human > rat > dog. Whereas
selexipag was inactive at EP2 and EP4 receptors, ACT-333679 was weakly active at the EP2 receptor,
but similar active at the dog EP4 receptor (EC50 value of 18 nM) compared to the IP receptor.
In human pulmonary arterial smooth muscle cells, ACT-333679 increased the intracellular cAMP
concentration with an EC50 value of 265 nM (re-calculated free EC50 value of 7.4 nM) and was a partial
agonist (31% of the maximum response).
Agonist-activated G protein-coupled receptors (GPCR) couple to G proteins to induce a cellular
response, and are subsequently phosphorylated by the G protein-coupled receptor kinases (GRKs); the
GRK-phosphorylated receptor then acts as a substrate for the binding of arrestins, which uncouple the
receptor and G protein, desensitizing the agonist-induced response and leading to the development of
tachyphylaxis (review in Kelly et al. 2008). In CHO cells expressing the IP receptor, ACT-333679 and
selexipag had lower efficacy in recruiting β-arrestin and in inducing internalization of the IP receptors
compared to prostacyclin analogues (iloprost, treprostinil and beraprost). The potencies of the
compounds in the cAMP assays were considerably shifted leftward versus the β-arrestin assay (free
EC5o values for selexipag and ACT-333679 were: 0.58 nM and 0.031 nM in the cAMP assay, 13 nM and
1.4 nM in the ß-arrestin assay). It is hypothesized by the Applicant that due to the partial agonism in
the desensitization pathway, ACT-333679 and selexipag might induce reduced tachyphylaxis in vivo.
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IP receptor activation induces vascular smooth muscle relaxation through PKA-mediated myosin light-
chain kinase (MLCK) phosphorylation (Merritt et al. 1991), and in cultured pulmonary arterial smooth
muscle cells selexipag and metabolite ACT-333679 induced vascular smooth muscle relaxation with
EC50 values of 157 and 4.3 nM, respectively (the re-calculated free EC50 values were 2.5 nM and 0.12
nM, respectively), via a stimulation of PKA-mediated MLCK phosphorylation.
PGI2 analogues inhibit the proliferation of human pulmonary arteries via a cAMP-dependent pathway
(Clapp et al. 2002), and cell cycle progression from G1-to S-phase is inhibited by block of CRE- and
pocket protein-dependent cyclin A gene expression (Kothapalli et al. 2003). ACT-333679 inhibited the
platelet-derived growth factor (PDGF)-mediated 3Hthymidine uptake in cultured human pulmonary
artery smooth muscle cells (hPASMC) with an IC50 value of 400 nM and the platelet-derived growth
factor-BB (PDGF-BB)-induced proliferation of human pulmonary arterial smooth muscle cells (PASMC)
with an IC50 value of 2.9 nM (the re-calculated free IC50 value was 0.081 nM).
TGF-ß1 is a cytokine involved via a production of reactive oxygen species (ROS) in the process of
pulmonary fibrogenesis (review in Todd 2012), and IP receptor activation via the PKA-dependent
inhibition of Ras/MEK/ERK signaling inhibits synthesis of extracellular matrix proteins induced by pro-
fibrotic mediators such as PDGF-BB and TGF-ß1 (Stratton et al. 2001 and 2002). ACT-333679 (0.1 -
10 µM) reduced TGF-ß1-stimulated up-regulation of collagen production on normal human lung
fibroblast cells (NHLF) and had anti-fibrotic activity. Furthermore, ACT-333679 inhibited platelet-
derived growth factor-BB (PDGF-BB)-induced and transforming growth factor-ß1 (TGF-ß1)-induced
extracellular 3Hproline incorporation, a measure of extracellular matrix synthesis, in primary normal
human lung fibroblasts (NHLF) with an IC50 value of 9.7 nM (the re-calculated free IC50 value was 0.27
nM).
The IC50/EC50 values for free selexipag and ACT-333679 are lower compared to the Ki values obtained
in binding experiments, indicating the presence of spare IP receptors. This hypothesis is supported by
the observation that in humans, values for therapeutically effective free maximum plasma
concentrations are 0.12 nM for selexipag and 0.28 nM for ACT-333679 following administration of the
1600 μg b.i.d. dose. These concentrations are in the range of the IC50/EC50 values and, therefore,
sufficient to stimulate the IP receptors. The existence of differences in spare IP receptors together with
differences in the degrees of signal amplification of the IP receptor signaling cascade can explain the
different potencies of selexipag/ACT-333679 in functional assays performed in different in-vitro test
systems.
Mice were used in the carcinogenicity studies and rabbits in the reproductive and developmental
toxicity studies performed with selexipag. There are marked species differences in the affinity/potency
of selexipag and ACT-333679 at the IP receptor. In order to give an explanation for the findings
observed in mouse carcinogenicity studies and in the rabbit reproductive and developmental toxicity
studies, the Applicant has provided results from a new study in which in vitro potencies (EC50 values),
as measured by cAMP accumulation, were determined in recombinant cells expressing similar levels of
the mouse, rabbit, or human IP receptor. EC50 values for selexipag and ACT-333679 were: 22 uM and
960 nM, respectively, at the rabbit IP receptor, 25 uM and 730 nM, respectively, at the mouse IP
receptor (based on total concentrations). Rabbit and mouse IP-receptors have 61and 69-fold lower
potencies for selexipag and 74- and 56-fold lower potencies for ACT-333679, respectively, compared
to humans (based on total concentrations).
In-vivo:
Selexipag decreased the mean arterial blood pressure and increased the heart rate (in normotensive
rats at i.d. doses of 10 mg/kg for MAP and > 3 mg/kg for HR; in conscious spontaneous hypertensive
rats (SHRs) at oral doses of 1 - 10 mg/kg) and increased femoral skin blood flow in anaesthetized rats
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(at i.d. doses of 1 - 10 mg/kg). No tachyphylaxis was observed after 4 weeks of administration in
anaesthetized rats or after 10 days of administration in SHR.
Two models of PH in rats were used: (1) the rat monocrotaline (MCT) model of PH (Chesney 1973) is
characterized by pulmonary hypertension (elevated right ventricular systolic pressure, cor pulmonale),
medial thickening and endothelial dysfunction in the pulmonary artery and right ventricular
hypertrophy (RVH) (Meyrick et al. 1980, review in Gomez-Arroyo 2012); MCT is activated to a reactive
metabolite in the liver which is transported to the lung, where it initiates endothelial injury (review in
Wilson et al. 1992); (2) the Sugen-hypoxia model of PH was developed from the observation that an
inhibition of the VEGF receptor 2 with Sugen 5416 (a VEGF receptor 2 blocker) in combination with
chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe
pulmonary hypertension, since in this model chronic reduction of the alveolar oxygen pressure elicits
pulmonary arterial vasoconstriction and vascular remodelling of the distal branches of pulmonary
arteries leading to PH (Taraseviciene-Stewart 2011). In MCT-PH Wistar rats, selexipag had the
following effects: 5 days of repeated selexipag administration (10 mg/kg, p.o., b.i.d.) decreased
pulmonary arterial pressure (PAP) without affecting the HR, and the efficacy of selexipag was
maintained over the 5-day treatment period; selexipag at 1 mg/kg twice daily for 19 days suppressed
the increase of RVSP and RVH in MCT-induced PH rats; MCT-induced PH accompanied by hypertrophy
of the pulmonary artery was suppressed by selexipag orally administered at 1 mg/kg twice daily for 19
days; oral administration of selexipag at 1 mg/kg twice daily for 19 days ameliorated the attenuated
acetylcholine-induced relaxation of PGF2α-pre-contracted pulmonary arteries; right ventricular
hypertrophy was suppressed by the oral administration of selexipag at doses of 1 and 3 mg/kg twice
daily for 19 days; the survival of MCT-treated rats was prolonged by selexipag orally administered at a
dose of 1 mg/kg twice daily for 45 days.
In conscious Sugen-hypoxia PH rats, selexipag at oral doses of 3, 10 and 30 mg/kg dose-dependently
decreased mean pulmonary arterial pressure (MPAP), MAP and core body temperature, and increased
HR and tail temperature. The effects of selexipag on pulmonary (MPAP decrease) and peripheral
haemodynamics (peripheral vasodilation leading to tail temperature increase) correlated, which
indicates that selexipag shows no selectivity for pulmonary vs. peripheral arteries.
Secondary pharmacodynamic studies
Neither selexipag nor ACT-333679 tested at concentrations of up to 10 µM had marked effects in 69
enzyme and radioligand binding assays.
Selexipag and ACT-333679 induced a concentration-dependent increase of intra-platelet cAMP in
human platelets with EC50 values of 40 μM and 550 nM, respectively (the re-calculated free EC50
values were 120 nM and 2.2 nM, respectively). The maximal elevation of cAMP induced by both
selexipag and ACT-333679 was lower compared to other IP receptor agonists, indicating that ACT-
333679 is a partial agonist of the IP receptor. 10 µM ADP-induced platelet aggregation was inhibited
with IC50 values of 4655 nM for selexipag and 121 nM for ACT-333679; at a lower ADP concentration
of 3 μM, the potency of ACT-333679 was higher (IC50 value of 74 nM). Selexipag inhibited platelet
aggregation induced by ADP in platelet-rich plasma from humans and monkeys with IC50 values of 5.5
and 3.4 μM, respectively (the re-calculated free IC50 values were 17 nM and 0.84 nM, respectively),
but showed a very weak inhibition in dogs (IC50 value >100 μM), and ACT-333679 inhibited platelet
aggregation in platelet-rich plasma from humans, monkeys, dogs and rats with IC50 values of 0.21,
0.21, 25 and 10 μM, respectively. The effects of a single i.d. dose of 10 mg/kg selexipag on thrombus
formation in rat femoral artery induced by 10% (w/w) ferric chloride (FeCl3) in vivo consisted of a
prolongation of the average time to occlusion (TTO).
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Safety pharmacology programme
In rats, selexipag had no effects on the central nervous system at doses of up to 30 mg/kg. At a dose
of 10 mg/kg, selexipag did not affect respiratory function, whereas at higher doses of selexipag (≥ 30
mg/kg) transiently increased respiration rate, tidal volume and minute volume were observed.
No marked effects of selexipag and ACT-333679 at micromolar concentrations were observed on hERG
channels expressed in CHO cells. Force and rate of contraction were not markedly affected by
selexipag and ACT-333679 in isolated right atria from guinea pigs. In isolated guinea pig papillary
muscles, selexipag shortened the action potential duration in a concentration-dependent manner at
concentrations of 10 - 100 µM. After administration of single oral doses of selexipag to conscious male
Beagle dogs, MAP decreased at doses ≥ 1 mg/kg and HR increased at doses of > 3 mg/kg, and at
doses of > 1 mg/kg the QT interval shortened, which seemed to be caused by HR changes since QTcF
intervals were not affected.
In male Sprague-Dawley rats, single oral administration of selexipag did not have marked effects on
bleeding time, PT or APTT at doses of up to 100 mg/kg.
In the isolated rat uterus, ACT-333679 at concentrations of 30 and 100 μM decreased the frequency of
spontaneous contractions.
In male Sprague-Dawley rats, oral administration of selexipag decreased urinary Cl− secretion and
Na+/K+ ratio dose-dependently at doses of 10 - 100 mg/kg, and urinary Na+ excretion and urine
volume slightly decreased at 30 and 100 mg/kg. These effects are known effects of IP receptor
agonists.
Pharmacodynamic drug interactions
In fasted Sprague-Dawley rats, oral administration of single doses of 10, 30 and 100 mg/kg selexipag
inhibited intestinal transport of charcoal, and i.d. doses of 10 - 100 mg/kg decreased the total acid
output of gastric juice.
Contractile EP3 receptors are implicated in emesis and diarrhoea (Kan et al. 2002) and are located on
the rat gastric fundus (Morrison et al. 2010). Neither selexipag nor ACT-333679 at concentrations of 1
mM contracted rat fundus, whereas the nonselective PGI2 analogues iloprost, beraprost and
treprostinil contracted rat fundal strips, which was antagonized by an EP3 receptor antagonist.
Selexipag and ACT-333679 did not have synergistic effects with contractile α1ARs in rat femoral
arteries, whereas activation of EP3 receptors by non-selective analogues of PGI2 is enhanced by α1AR
stimulation.
Both PGE2 and PGI2 reduce the threshold of nociceptor sensory neurons to stimulation (review in
Smyth et al. 2009). IP prostacyclin receptor agonists have the potential to induce neurogenic pain
(Bley et al. 1998, review in Rahman et al. 2011).
2.3.3 Pharmacokinetics
The pharmacokinetic profile of selexipag was mainly characterized in the rat and dog, the species used
in the repeated dose toxicity studies.
Absorption
Selexipag was rapidly absorbed after oral administration in rats, dogs and monkeys with tmax values of
1 – 4 h. Selexipag exposure was lower than that to ACT-333679 in all species, and this difference was
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2-fold in monkeys, 6-fold in rats and 13-fold in dogs. After administration of selexipag, the oral
bioavailability of ACT-333679 was 57% in rats and 29% in monkeys. In rats, the pharmacokinetics of
selexipag after oral administration was linear to doses of 0.3 - 3 mg/kg. In rats, food intake did not
affect the extent of absorption of selexipag, and no sex differences in the pharmacokinetics were
observed. ACT-333679 was rapidly absorbed in the rat with an oral bioavailability of 57%.
Distribution
The selexipag-related radioactivity distributed rapidly through the whole body and the highest
concentrations were found in the liver followed by the gastro-intestinal tract, small intestine, stomach,
kidney, lung, i.e. in organs involved in the absorption and elimination of the substance. Selexipag
hardly passes the blood-brain-barrier. Tissue concentrations of radioactivity decreased in parallel with
the decrease in the plasma concentrations. In pigmented rats, limited binding of 14C-selexipag-related
radioactivity to melanin was observed.
Placental transfer of selexipag/metabolites was shown with maximum fetal radioactivity concentrations
of about 15% of maternal plasma concentrations representing altogether 0.01% of the dose.
Binding of selexipag and ACT-333679 in rat, dog, monkey and man sera was in a range of 97–99%.
Both substances bind to human serum albumin and α1-acid glycoprotein. Equilibrium dialysis studies in
mouse, rat, rabbit, dog, monkey, and man plasma gave free fractions of 0.3-0.6% for selexipag and
0.4-0.8% for ACT-333679. The volume of distribution at steady-state was 1.8-2.5 l/kg, i.e. in excess
of total body water in rats and dogs, indicating good tissue penetration.
Metabolism
Selexipag undergoes five types of primary biotransformation reactions, and the main pathway is
hydrolysis of the sulfonamide and formation of the pharmacologically active acid ACT-333679 via a
carboxylesterase-mediated reaction. Formation of ACT-333679 is the major metabolic pathway of
selexipag in all species, although some interspecies differences in terms of turnover as wells as of
metabolic profiles were observed. Hepatic microsomes from all tested species including humans are
able to form ACT-333679, whereas microsomes of the small intestines from all species including
humans are not able to hydrolyse selexipag. Selexipag was hydrolysed to ACT-333679 in plasma of rat
and mouse, whereas little or no degradation occurred in plasma of dog, rabbit, cynomolgus monkey
and man. Metabolism of ACT-333679 was lower compared to selexipag in all tested species including
human. Therefore, whereas ACT-333679 formation in rabbit, dog, cynomolgus monkey and human is
mostly catalysed by hepatic microsomal enzymes, in the mouse and rat - in addition to hepatic
microsomal enzymes - carboxylesterases present in plasma are also responsible for selexipag
hydrolysis and formation of ACT-333679. CYP2C8 is mainly involved in the formation of MRE-6300 (a
hydroxylated metabolite of ACT-333679), and CYP3A4 is also involved. Human UGT1A3 is involved in
the glucuronidation of ACT-333679 to the acyl glucuronide P11 followed by UGT2B7.
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Figure 2: The proposed metabolic pathways of selexipag in rat, dog, and human.
Excretion
In rats, biliary excretion was the major elimination pathway of selexipag after either the oral or
intravenous route of administration accounting for about 90-95% of the absorbed dose, and renal
elimination of hydrophilic metabolites was much less important (0.9 - 4.7% of the dose). In dogs,
biliary excretion was also the main excretion pathway (80 - 89% of total radioactivity), whereas renal
excretion was much less important (< 2% of total radioactivity).
Selexipag and/or its metabolites transferred into milk. The exposure to radioactivity was 2.5-fold
higher in milk than in plasma.
Pharmacokinetic drug interactions
Both selexipag and ACT-333679 possess good membrane permeabilities, and this behaviour seems to
be primarily responsible for the tissue distribution of these substances. In rats, selexipag administered
orally for 7 days at doses of 1 and 10 mg/kg/die had no effect on drug-metabolizing liver enzymes.
Selexipag and ACT-333679 inhibited CYP2C8, CYP2C9, CYP2D6 and CYP3A4 activities at supra-
therapeutic micromolar concentrations, and both substances did not affect the human multidrug
resistance protein MDR-1 (ABCB1, P-gp). Selexipag is a weak substrate of human P-gp indicating that
P-gp is involved in the transport of selexipag through the cell monolayers, whereas ACT-333679 is not
a substrate of P-gp. Selexipag is a weak substrate for both OATP1B1 and OATP1B3 transporters, and
ACT-333679 is also a weak substrate for OATP1B3. Selexipag and ACT-333679 inhibited the activities
of both OATP1B1 and OATP1B3 transporters only at supra-therapeutic micromolar concentrations.
Selexipag is not a BCRP substrate, whereas ACT-333679 is a BCRP substrate. At micromolar
concentrations, both selexipag and ACT-333679 inhibited OAT1-, BCRP-, BSEP-, OAT3- and MATE1-
transporters, and ACT-333679 also inhibited the MRP2-transporter. In human hepatocytes, both
selexipag and ACT-333679 induced CYP isoenzyme mRNAs with the following free EC50 values: 20
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nM/90 nM for CYP3A4, 6 nM/29 nM for CYP2C9. These free EC50 values are above therapeutically
effective free plasma concentrations (0.12 nM selexipag, 0.28 nM ACT-333679). However, assuming a
luminal selexipag concentration of 1.3 µM and a free selexipag concentration in enterocytes of 8 nM,
clinically relevant induction of CYP3A4 and CYP2C9 in the gut cannot be excluded. Therefore, the
administration of selexipag at the highest proposed dose in PAH patients (1600 µg b.i.d.) could be an
inducer of both CYP3A4 and CYP2C9 in the intestine. Although in a study in healthy subjects, selexipag
(400 µg b.i.d.) did not alter the exposure to S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4
substrate) after a single dose of 20 mg warfarin, interactions with CYP2C9 and CYP3A4 in humans
treated with the highest proposed dose have not been studied and thus potential interactions at
clinically relevant concentrations cannot be ruled out.
In conclusion, based on the re-calculated free concentrations of selexipag and ACT-333679 in the in-
vitro pharmacokinetic interaction studies, selexipag and its metabolite do not seem to have any
relevant inhibitory potential on CYP P450 enzymes, on transport proteins or on BCRP in the gut.
However, an induction of CYP3A4 and CYP2C9 by selexipag in the gut cannot be excluded.
2.3.4 Toxicology
Single dose toxicity
Single dose toxicity of selexipag was determined in Slc:ddY mice, Slc:SD rats and Beagle dogs. The
maximum non-lethal i.v. dose of selexipag was 40 mg/kg in mice and rats. After oral dosing the
maximum non-lethal dose of selexipag was 250 mg/kg in rats and 200 mg/kg in male dogs.
Repeat-dose toxicity
Repeat-dose toxicity of selexipag was determined in B6C3F1/Crlj mice, SD rats and Beagle dogs.
In mice, liver weight increased (at doses of 300 mg/kg/day in a 13 week study), correlating
histologically with hypertrophy of centrilobular hepatocytes, and these alterations seemed to be related
to the induction of drug-metabolizing enzymes.
In rats, selexipag-induced mortality occurred in repeated dose toxicity studies in rats after oral
treatment at doses of ≥ 500 mg/kg/day and was related to marked vasodilation induced by selexipag.
The primary clinical symptoms after oral administration of selexipag were flush, red discoloration of
pinna/limbs/abdomen and flaccidity linked to IP receptor-dependent vasodilation and blood pressure
decrease (at doses of > 6 mg/kg/day). Selexipag increased urine volume accompanied by a decreased
excretion of Na and K (at doses of > 25 mg/kg/day), which might be explained by the vasodilating
effects of selexipag which induced an increase in renal blood flow and an enhancement of urine
production. Increased adrenal weight (at doses of ≥ 25 mg/kg/day) associated with cortical
hypertrophy and hypertrophy of the zona glomerulosa seems to be a stress-related response. At high
oral doses (> 100 mg/kg/day), the administration of selexipag induced increased liver weight
associated with hypertrophy of centrilobular hepatocytes and proliferation of the smooth endoplasmatic
reticulum of hepatocytes as demonstrated in electron microscopic examinations; these findings might
be explained by an induction of hepatic drug-metabolizing enzymes by selexipag. These effects might
also be responsible for the increased thyroid weights accompanied by hyperplasia of the follicular cells
in the thyroid (≥ 25 mg/kg/day). Platelet count dose-dependently decreased at doses of ≥ 6
mg/kg/day in males and at doses of ≥ 20 mg/kg/day in females. The Applicant was not able to provide
a mechanistic explanation for this effect observed in rats. Due to the minor effect, the reversibility of
the effect and the absence of effects on coagulation times or bleeding, the rat finding of decreased
platelet counts after administration of selexipag seems to have no human relevance. Furthermore,
decreased platelet count has also been observed after administration of other IP receptor agonists in
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rat repeated-dose toxicity studies (e.g. for treprostinil). Haemorrhage in the alveoli of lungs at doses of
> 20 mg/kg/day selexipag might be explained by the platelet-inhibitory effects of selexipag.
Dogs were the more sensitive species compared to rats in repeated dose toxicity studies performed
with selexipag. In juvenile dogs, the major clinical findings were related to selexipag-induced
disturbance of intestinal motility leading to the development of intussusception with changes in stool,
prolapse of anus and dark red discoloration in the jejunum and intussusception (jejunum), which
manifested histologically as haemorrhagic infarction (necrosis, haemorrhage and congestion of the
intestinal mucosa; at doses of > 2 mg/kg/day). Intussusception was the cause of death (3 animals at a
dose of 20 mg/kg/day in the 14 day study, 2 animals at a dose of 4 mg/kg/day in the 39 week study).
The mechanism for the development of gastrointestinal alterations induced in dogs by selexipag has
been discussed by the Applicant. In contrast to other prostaglandins, prostacyclin (PGI2) prevents
diarrhoea caused by other prostaglandins, PGI2 inhibits gastric acid secretion and is cytoprotective for
the stomach and the small intestine, and the antidiarrheal activity of PGI2 may be due to its
antipropulsive effects (Ruwart and Rush 1984). Administration of the prostacyclin analogue taprostene
induced hypermotility of the gastrointestinal tract resulting in intestinal invagination (intussusception)
in dogs (Wöhrmann et al. 1994). Intussusception is defined as prolapse of a proximal bowel segment
into a distal segment and may result in luminal obstruction, mucosal congestion or infarction.
Intussusception is more common in young dogs (< 6-8 month old; Merck Veterinary Manual), which is
the age of affected dogs in repeated dose toxicity studies performed with selexipag. Intussusception is
the most important cause of gastrointestinal obstruction in dogs (Mutasa et al. 1994). In humans,
intussusception is rare in adults and mainly observed in association with cancer, but it is relatively
common in children (Azar and Berger 1997, Duijff et al. 2007). The Applicant suggests that
intussusception is a result of exaggerated pharmacodynamics of selexipag in dogs. The risk for humans
to develop intussusception is considered low by the Applicant in view of the particular sensitivity of
dogs to IP receptor agonist-induced effects on intestinal motility, the increased sensitivity of young
dogs to develop intussusception and the safety margins for a human dose of 1600 µg b.i.d. According
to the Applicant, no case of intestinal invagination was reported during the clinical studies with
selexipag.
Intussusception did not occur in mouse or rat toxicity studies. However, in our view, safety margins at
the NOEL of 1 mg/kg/day regarding the gastrointestinal findings in dogs as obtained in the 39 week
study, corrected for species difference in receptor potency, are very low with values of 0.1 for
selexipag and 1 - 1.6 for ACT-333679, respectively, in relation to human exposure at a dose of 1600
µg b.i.d.. Therefore, the possible induction of gastrointestinal disturbances denoting intestinal
intususception (manifested as ileus or obstruction) induced by selexipag has been included as an
important potential risk in the Risk Management Plan, and special caution is needed in the treatment of
children, since children (and also young dogs) are more susceptible than adults to the induction of
intussusception (Azar and Berger 1997, Duijff et al. 2007).
The second most marked effect aside from the gastrointestinal effects observed in repeated dose
toxicity studies in dogs performed with selexipag were bone and bone marrow alterations. These
consisted of increased ossification of the trabeculae and periosteum and bands of fibroblasts with
collagen fibres ("fibrosis") in the femur and sternum (at doses of > 6 mg/kg/day in the 14 day study,
> 3 mg/kg/day in the 4 weeks study and at all doses (> 1 mg/kg/day) in the 39 weeks study).
Furthermore, the amount of hematopoietic tissue in the bone marrow of the femur and sternum was
affected: it decreased at doses of > 6 mg/kg/day in the 14 day study and > 3 mg/kg/day in the 4
week study, but increased at all doses (> 1 mg/kg/day) in the 39 week study. Extramedullary
haematopoiesis in the spleen was observed at a dose of 6 mg/kg/day in the 4 week study. In the 39
week repeated dose toxicity study in dogs, a NOAEL could not be established for bone/bone marrow
findings. Increased bone mass was still observed after 4 weeks of recovery in the 4-week dog toxicity
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study. The increased ossification was not associated with clinical signs indicative of pain or changes in
blood chemistry. Increased ossification was associated with changes in the bone marrow, including
bands of fibroblasts with collagen fibres ("fibrosis") and altered appearance of the hematopoietic tissue
in femur or sternum (either decreased or increased haematopoiesis).
Increased ossification of femur and sternum was also reported in the juvenile dog study. In the
juvenile study, no effects were noted on limb function or on growth measurements like tibia length and
standing shoulder height.
The observation that ACT-333679 was similarly active at the dog EP4 receptor (EC50 value of 18 nM)
compared to the dog IP receptor (EC50 value of 14 nM), but was inactive at the human EP4 receptor,
plays a central role in the assessment of human relevance of the bone findings observed in dogs.
Therefore, in repeated dose toxicity studies performed with selexipag in dogs both IP and EP4
receptors are stimulated (the first by both selexipag and ACT-333679, the latter by ACT-333679).
PGE2 can activate formation of the periosteal and endocortical surface of long bones in both the rat
and dog, which involves the recruitment and proliferation of osteo-progenitor cells present in the
periosteum and mesenchymal cells of the marrow cavity; furthermore, prostaglandins activate
remodelling activity on the surface of trabeculae and in the cortex of long bones indicating that
prostaglandins are involved with increases in both bone formation (stimulation of osteoblasts) and of
bone resorption (stimulation of osteoclastic bone resorption; review in Norrdin et al. 1990). PGE2
increases bone mass in animals and humans; stimulation of the EP2 receptor stimulates formation,
stimulation of the EP4 receptor stimulates resorption (and possibly formation), and stimulation of the
FP receptor produces new trabeculae (review in Hartke and Lundy 2001). The EP4 prostanoid receptor
is one of 4 receptor subtypes for prostaglandin E2 and belongs to the family of G protein–coupled
receptors, is coupled to Gsa and stimulates AC activity and cAMP production, but is also associated with
Gi, phosphatidylinositol 3-kinase (PI3K), ß-arrestin and ß-catenin (review in Yokohama et al. 2013).
The following observations indicate that the EP4 receptor has a major role in bone biology: the
administration of selective EP4 receptor agonists has been demonstrated to reverse osteoporotic
changes, enhances the bone-implant interface strength and has a synergistic effect when used with
other bone cell targeting pharmacological agents such as BMP-2 and bisphosphonates (review in
Pagkalos et al. 2012); PGE2 promotes both bone resorption and bone formation, and these effects are
mediated by EP4 signalling (review in Yokohama et al. 2013); ONO-4819, which is a prostaglandin (PG)
E2 EP4 receptor selective agonist (EP4A), accelerates BMP-induced osteoblastic differentiation of the
pluripotent stromal cell line ST2 by stimulating the commitment for osteoblastic lineage (Nakagawa et
al. 2007); using a selective EP4 receptor antagonist, it was demonstrated that PGE2 stimulates
osteoblastic commitment of rat bone marrow stromal cells (BMSC) via activation of the EP4 receptor
(Shamir et al. 2004); results from studies in EP4 receptor knockout mice indicated that the EP4
receptor resulted in an imbalance in bone resorption over formation leading to a negative bone balance
and that the absence of the EP4 receptor decreases bone mass and impairs fracture healing in aged
male mice, leading to the conclusion that the EP4 receptor is a positive regulator in the maintenance of
bone mass and fracture healing (Li et al. 2005); osteoblasts and bone marrow adipocytes are derived
from a common bone marrow mesenchymal progenitor, and a PGE2 receptor subtype 4 agonist
stimulated bone formation at skeletal sites with hematopoietic and fatty marrow and simultaneously
decreased fatty marrow area and the number of adipocytes in the bone marrow (Aguierre et al. 2007).
"Fibrosis", characterized by bands of fibroblasts with collagen fibres, observed at high doses of
selexipag administered in the repeated dose toxicity studies in dogs resembles callus tissue during the
process of fracture healing, and local infusion of PGE2 has been demonstrated to cause stimulation of
callus formation in rabbits (Keller et al. 1993). Therefore, "fibrosis" was induced by high doses of
selexipag via activation of the EP4 receptor and seems to be similar to bone fracture healing.
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The observation that in the repeated dose toxicity studies performed in dogs with selexipag the
amount of haematopoietic tissue in the bone marrow of the femur and sternum was affected (either
increased or decreased) is in line with the finding that PGE2 has both stimulatory and inhibitory effects
on the differentiation of haematopoietic progenitors.
The following observations indicate that PGE2 has inhibitory effects on the differentiation of
haematopoietic progenitors: PGE1 and PGE2 inhibit the proliferation of committed myeloid stem cells
(Kurland et al. 1978); prostaglandins inhibit the in-vitro growth of erythroid progenitor cells obtained
from patients with chronic renal failure (Taniguchi et al. 1989); prostaglandin inhibitors may have a
role in combination with hematopoietic growth factors in accelerating hematopoietic recovery following
cytoreductive chemotherapy (O´Reilly and Gamelli 1990); the in vivo administration of IL-1 results in
neutrophilia and generation of myelopoietic suppressive effects mediated by cyclooxygenase pathway
products; blockade of PG synthesis abrogates the myelopoietic suppressive effects associated with IL-1
administration and optimizes its myelopoietic stimulatory capacity (Pelus 1989); intravenous injection
of PGE2 resulted in the suppression of nucleated bone marrow and splenic cellularity, total resident
nucleated peritoneal cells and the number of granulocyte-macrophage progenitor cells (Gentile et al.
1983).
However, the following observations indicate that PGE2 has also stimulatory effects on the
differentiation of hematopoietic progenitors: using a murine bone marrow stem cell assay, it was
demonstrated that lipoxygenase products stimulate myeloid colony formation and lymphoid stem cell
proliferation (Vore et al. 1989); in the bone marrow, PGE2 expands hematopoietic stem cells and
affects the differentiation of haematopoietic progenitors, and PGE2 treatment expands hematopoietic
stem cells with no negative impact on haematopoietic progenitors (Frisch et al. 2009); PGE2 regulates
hematopoietic stem/progenitor cell (HSPC) activity and the EP4 receptor was identified as the key
receptor for PGE2-mediated regulation of HSPCs via stimulation of PKA and ß-catenin (Ikushima et al.
2013). Furthermore, two mechanisms of prostanoid activation of erythropoiesis have been proposed:
1. Activation of the erythroid progenitor cells in the bone marrow by PGE2 and PGD2 to increase the
responsiveness of erythroid cells to erythropoietin, and 2. stimulation of renal erythropoietin
production by hypoxia via the prostacyclin pathway (review in Fisher and Hagiwara 1984).
In conclusion, as metabolite ACT-333679 is similarly active on both IP and EP4 receptors from dogs,
the bone/ bone marrow effects in dogs induced by selexipag in the repeated dose toxicity studies
might be related to effects of ACT-333679 on the EP4 receptor. Because both selexipag and its
metabolite ACT-333679 have no affinity for the human EP4 receptor, the bone/bone marrow effects
induced by selexipag in dogs; this effect is species-specific and, therefore, not relevant to humans.
As observed in rats, decreased platelet counts (at doses of > 6 mg/kg/day) have been found in dogs.
This effect might be IP receptor mediated because in anaesthetized dogs the infusion of prostacyclin
has been demonstrated to produce splenic dilation that leads via blood pooling to a decrease in
circulating blood cell concentrations (Noguchi et al. 2006). For the assessment of possible effects of
selexipag on the bone marrow, see also the clinical assessment of questions 131 and 132.
Reduced urinary excretions of Na, K and Cl (at doses of > 6 mg/kg/day) induced by selexipag might be
explained by the vasodilating effects of selexipag.
Toxicokinetic evaluation of repeated-dose studies
Binding of both unchanged selexipag and its metabolite ACT-333679 in rat, dog, monkey, and man
sera was in a range between 97–99%, and equilibrium dialysis in mouse, rat, rabbit, dog, monkey, and
man plasma gave free fractions of 0.3-0.6% for selexipag and 0.4-0.8% for ACT-333679. Therefore,
both selexipag and ACT-333679 exhibited no marked species differences in the extent of serum protein
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binding among rats, dogs, monkeys and humans, and no correction of the exposure ratios for plasma
protein binding is necessary.
However, it should be taken into account that both selexipag and ACT-333679 have species differences
at the target IP receptor, with sensitivity in the order human > rat > dog (the EC50 values for free
substances at the human, rat and dog IP receptors were 4, 170 and 1100 nM for selexipag,
respectively, and 0.17, 3.1 and 14 nM for metabolite ACT-333679, respectively). When the exposure
ratios at the NOAEL of 6 mg/kg/day in rats and at the LOEL of 1 mg/kg/day in dogs are corrected for
the species-dependent EC50 values at the IP receptor, values for the exposure ratios for rats at the
NOAEL obtained in the 26 week study are 0.04 - 0.08 for selexipag and 0.6 - 1.4 for ACT-333679, and
for dogs at the LOEL obtained in the 39 week study are 0.1 for selexipag and 1 - 1.6 for ACT-333679,
respectively.
Genotoxicity
A standard battery of genotoxicity test was performed with selexipag and the active metabolite ACT-
333679. In conclusion, selexipag and its metabolite ACT-333679 were tested in vitro in AMES and
chromosome aberration assays and in vivo in mouse bone marrow micronucleus and rat liver Comet
assays with no biologically relevant adverse observations.
Carcinogenicity
Two GLP-conform carcinogenicity studies were performed in B6CF1/Crlj mice and SD rats.
In the mouse study there was no treatment-related increase in either number of tumours or tumour
bearing animals in either sex. Slightly higher incidence of thyroid follicular cell tumours (adenoma and
carcinoma) were observed in 2 males each in the 250 and 500 mg/kg groups and in 3 females in the
500 mg/kg group, although there were no statistically significant differences in either trend analysis or
pairwise comparison between the control and any dose group. This was paralleled by increased
incidence and severity of hyperplasia/hypertrophy of the follicular cells. Follicular cell adenoma was
also observed in 1 female each at doses of 125 and 250 mg/kg, respectively. A treatment related
effect cannot be completely excluded, since increased incidence and severity of
hyperplasia/hypertrophy of the follicular cells were also observed in these groups. Safety margins for
neoplastic findings at the NOEL of 125 mg/kg/day of 172-fold for selexipag and 54-fold for ACT-
333679 were calculated towards AUC exposure levels at the clinical dose of 1600 µg b.i.d.
A mechanistic study performed in mice (T-13.030) revealed that selexipag induces the expression and
activity of hepatic metabolic enzymes and plasma levels of T3 and TSH, which explains a continuous
stimulation of the thyroid and subsequent hyperplasia and adenoma. This mechanism is rodent specific
(Klaassen 2001, De Sandro 1991, Hood 1999]. Even so an increase in TRH and prolactin levels have
not directly been demonstrated in mice treated with selexipag, the mechanistic study implies a
dysregulation of the hormonal axis of the thyroid induced by liver enzyme induction and compensatory
increases in TSH and TRH. Given the fact that rodents are more susceptible to thyroid hormone
imbalances (Capen 1996) and these mechanisms are often rodent specific (Klaassen 2001, De Sandro
1991, Hood 1999) and hepatic enzyme induction has not been observed in clinical trials, these findings
are not of toxicological concern.
In female mice ovarian corpora luteal hypertrophy, mammary gland lobular hyperplasia, and vagina
mucification was observed at doses of ≥ 125 mg/kg (low dose) which hint to elevated levels of
prolactin. Yamada et al. (2006) have shown that thyrotropin-releasing hormone (TRH) knock-out mice
display slightly reduced prolactin levels; prolactin suppression was more pronounced during lactation in
knock-out animals. This indicates that increased TRH levels result in increased prolactin levels
(reviewed in Ben-Jonathan N et al 2008). Increased TRH levels might be triggered by hepatic
microsomal enzyme induction and is in line with observed increased centrilobular hepatocellular
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hypertrophy at doses of ≥ 125 mg/kg. Enzyme induction in mouse livers by selexipag has been
studied in the mechanistic study (T-13.030) and led to compensatory increased T3 and TSH levels in
treated mice. However, TRH levels have not been measured in this study but are likely to be
compensatory elevated.
The incidence of fibro-osseous lesions increased in high-dose males. This lesion frequently occurred in
female mice in the control and all treatment groups, indicating that it is a background finding in aging
animals. The mechanism of these findings in high-dose males is unclear, however occurred at
sufficiently high safety margins (NOAEL 250 mg/kg) of > 100-fold for selexipag and ACT-333679,
respectively.
In the rat study there were no effects of selexipag on survival rate of males. A statistically significant
trend of an increase in the survival rate with increasing dose levels was observed in females, and the
survival rate of the 100 mg/kg group was significantly higher than that of the control group.
There was no treatment-related increase in either number of tumours or tumour bearing animals in
either sex. A decrease in the number of benign tumours was observed in males in the 30 and 100
mg/kg groups. Decreases in the total number of tumours, number of malignant tumour bearing
animals and number of multiple tumour bearing animals were observed in males in the 100 mg/kg
group.
Marginally increased incidence of Leydig cell tumour was observed in the 100 mg/kg group, and
statistically significant positive trend was noted (rare tumour, p<0.025); however, there was no
statistical significance in pairwise comparison between the control and 100 mg/kg groups. Additionally,
slightly higher incidence in focal hyperplasia of Leydig cells was observed in this group. The tumour
incidence of the 100 mg/kg group (5/60 animals, 8%) was marginally higher than that of historical
data (0 to 4% in the incidence). In addition, there was no statistically significant positive trend in
incidence of Leydig cell tumour in the control, 10 and 30 mg/kg groups.
In the pituitary, increased incidence of anterior adenoma was observed in males in the 10 mg/kg group
with statistical significance (common tumour, p<0.01). However, it was not considered to be treatment
related, since it was not dose-related.
Mechanistic studies performed with cultured rat Leydig cells (T-11.295) and in vivo in rats (T-11.460)
gave no conclusive explanation for the occurrence of Leydig cell adenoma in the rat carcinogenicity
study. Leydig cell hyperplasia and subsequent adenoma formation is usually a proliferative response to
increased testosterone, LH and/or prolactin levels in rats (reviewed in Cook JC 1999). In the in vitro
study with cultured Leydig cells, selexipag/ACT-333679 increased testosterone excretion at relevant
concentrations close to the Cmax in the rat carcinogenicity study. However, testosterone, LH and
prolactin levels were decreased in the in vivo mechanistic study using similarly high doses (up to 150
mg/kg/day). The reason for the decrease is not clear and cannot explain adenoma formation.
To this end rats are more sensitive in their proliferative response to LH and their sensitivity to
chemically induced Leydig cell tumours (Prentice 1995 and Cook 1999). Safety margins at the NOEL of
30 mg/kg/day based on AUC values are 19-fold for selexipag and 92-fold for ACT-333679 at the
clinical dose of 1600 µg selexipag b.i.d.. Taken together, due to the rat specific mechanism and the
high safety margins, Leydig cell tumours are not expected to occur in humans at the anticipated
maximum recommended human dose of 1600 µg b.i.d.
At ≥ 30mg/kg/day (NOAEL 10 mg/kg/day) eye dilation and meandering (tortuosity) of the retinal
arterioles were observed in the rat carcinogenicity which were not accompanied by histological lesions.
Ophthalmological findings were not observed in the other (shorter) repeat-dose toxicity studies.
Prostaglandins and prostacyclins have been described to dilate retinal arterioles and increase retinal
and choroidal blood flow via IP and EP2 receptors (Mori 2007a, Mori 2007b). Safety margins of 5.52-
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fold and 34.5-fold for selexipag and ACT-333679 towards human exposure at 1600 µg b.i.d.,
respectively, were calculated. As ophthalmological findings are probably an exaggerated
pharmacological effect mediated via the IP receptor, a correction factor of 29 for selexipag (EC50: 250
nM for human, 7200 nM for rat) and 18 for ACT-333679 (EC50 at IP receptor: 6.1 nM for human, 110
nM for rat) should be applied. This results in safety margins of 0.2x and 2x for selexipag and ACT-
333679, respectively. Therefore, ophthalmic findings might be of relevance for humans. However,
ophthalmological assessments have been implemented in phase 2 and phase 3 clinical studies. No
treatment-related findings of retinal vascular tortuosity by using fundus photography were observed.
Nevertheless, due to the low safety margins and limited long-term data in humans, ophthalmological
effects associated with retinal vascular system have been included as an important risk in the Risk
Management Plan.
Various non-neoplastic findings were observed in the mouse and rat carcinogenicity studies. Alterations
of the liver, thyroid and adrenal gland are consistent with those found in general toxicity studies.
Adaptive changes (hyperplasia or atrophy) in the thymus, fibro-osseous lesion in the femur,
erosion/ulcer, adhesion with surrounding tissues and/or mucosal regeneration in the glandular stomach
and hyperplasia of acinar cells in the pancreas were observed in mice and rats. Additionally, treatment-
related lesions in the female reproductive system (hypertrophy of corpora lutea, vaginal mucification,
lobular hyperplasia in mammary glands), in the sublingual gland (hypertrophy/atrophy of the acinar
cells), in the intestine/duodenum (perforation), in the spleen (increased pigment in the red pulp and
atrophy) and in the kidney (tubular hypertrophy of the papilla, eosinophilic droplet in papillary
epithelium, tubular basophilia in the cortex, tubular hypertrophy in outer medulla, hyperplasia of the
papillary epithelium, tubular regeneration and urinary cast) were found in mice. Finally, dilation and
tortuosity of retinal arterioles were observed only in rats at the end of the study.
The Applicant explained that the ovarian corpora lutea hypertrophy, mammary gland lobular
hyperplasia, and vagina mucification could be a consequence of an elevated prolactin level that could
be induced by a multistep process, starting with hepatic microsomal enzyme induction. Although these
alterations could be a consequence of elevated prolactin levels as the Applicant stated, hormonal
imbalance (increments in levels of prolactin and/or TRH and decrement in T3 levels) associated with
hypertrophy of ovarian corpora lutea that could produce a shift towards a progesterone-like phase of
the normal oestrus cycle and lead to vagina mucification have not been reported in animals treated
with selexipag. Moreover, decrements in prolactin levels were reported in male rats after selexipag
administration.
Reproductive and Developmental Toxicology
The reproductive and developmental toxicity of selexipag was studied according to ICH-S5 in GLP-
compliant studies in the rat and rabbit. During these studies standard parameters were assessed.
Toxicokinetic parameters were obtained from satellite animals. Pregnant rats showed a slightly higher
exposure towards selexipag and ATC-333679 compared to non-pregnant rats for the highest dose
group of 20 mg/kg bw.
In the study on fertility and early embryonic development in the rat, time until copulation was
significantly longer in the high dose group probably due to impaired oestrus of females. Although
fertility index and other female reproductive parameters were not affected, general effects on the
female reproductive system cannot be excluded.
An embryotoxicity study was performed in the rat, and the rabbit was chosen as non-rodent species
for the second embryotoxicity study. An altogether higher incidence for visceral anomalies was
observed in the rat study. However, the overall incidence was reported to be within the historical
control range and there was no significant difference in the incidence of any abnormality between the
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control and high-dose group. In the rabbit study, retrocarval ureter was observed with higher incidence
in the high dose compared to the control group, but was also shown to be within the historical control
range of the study facility. Receptor potency studies provided by the applicant showed much lower
potency of selexipag and ACT-333679 at the rat and rabbit IP-receptor compared to the human
receptor (refer to the pharmacology section above). Therefore, IP receptor mediated effects on
reproduction will probably not become evident during the reproductive toxicity studies since exposure
margins adapted to IP-receptor potency are usually below human therapeutic exposures. In
conclusion, selexipag did not show any teratogenic effects in the studies on embryo-fetal development.
Exposure margins, based on total exposure, were about 13-times for selexipag and 46-times for ACT-
333679 towards human therapeutic exposures.
In the pre/-postnatal development study performed in the rat, a delay in the cleavage of the
balanopreputial gland in males of the F1 generation was observed for all dose groups compared to
controls. However, otherwise functional development and reproductive performance of the F1
generation was not affected.
Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
Based on a dose-range finding study, a pivotal GLP compliant juvenile toxicity study was performed in
Beagle dogs. Dogs were 28 days of age at the beginning of the study.
In juvenile dogs, selexipag exposure was 2- to 3- fold lower than in adult animals at comparable doses
and remained constant after repeated dosing. Exposure towards ACT-333679 was only comparable to
adult exposure at the first day of dosing and decreased towards the end of the treatment period.
Like in the repeat-dose toxicity studies in adult dogs, mortality due to intussusception was observed in
juvenile animals. Other treatment-related changes mainly consisted of increased thickness of the
compact bone of the femoral shaft with increased numbers/thickness of trabeculae in the medullary
cavity which were noted in a time- and dose-related pattern. Similar bone effects and haematopoietic
hypercellularity were reported from the repeat-dose studies in adult dogs and were discussed to be
mediated through ACT-333579 species specific activation of the dog EP4 receptor. (see above)
A dose-dependent delay in the closure of the femoral and/or tibia epiphyseal growth plate was
observed in animals sacrificed at week 39, a finding which could affect growth of the skeleton. A
NOAEL for bone effects was not established. Bone effects as well as intestinal invagination have to be
carefully discussed as soon as selexipag will be considered for the treatment of the paediatric
population. Sexual maturation was also observed to be delayed in female dogs. It could be shown that
this delay was not due to a direct involvement of prostacyclin in uterine function, but was rather due to
toxicity of selexipag leading to low food consumption and a massive reduction in body weight gain and
low ovary and uterus weights. In conclusion, bone and intestinal effects are described in the SmPC
(Section 5.3). Reduced food consumption and consecutive effects were observed only at very high
doses so that the relevance is regarded low and inclusion in the SmPC is not warranted.
Local Tolerance
In rabbits after intravenous and paravenous application of selexipag, no local irritation was observed.
Other toxicity studies
All tested impurities were negative for revertant colonies in the performed Ames tests and can be
considered as non-mutagenic.
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2.3.5 Ecotoxicity/environmental risk assessment
The predicted concentration for surface water is correct based on the applicant’s assumption of the
number of patients. In addition, in 2015, the prevalence at orphan.net has even been reduced to
1.5/1,000,000. The assessor agrees that the PEC surface water is clearly below the action limit.
The test on the determination of the partition coefficient of ACT-293987 according to OECD 107 is valid
and plausible. It is agreed that no Phase I PBT assessment is necessary. The CHMP also agrees with
the applicant’s conclusion that there are no indications requiring an experimental Phase II assessment
irrespective of the action limit.
Table 1 Summary of main study results
Substance (INN/Invented Name):
CAS-number (if available):
PBT screening
Result
Conclusion
Bioaccumulation potential- log
Kow
OECD107
Log Dow = 3.86 (pH 5)
Log Dow = 2.26 (pH 7)
Potential PBT
N
Phase I
Calculation
Value
Unit
Conclusion
PEC
surfacewater
, default or
refined (e.g. prevalence,
literature)
0.000024
µg/L
> 0.01 threshold
N
Other concerns (e.g. chemical
class)
N
In conclusion, the environmental risk assessment of selexipag ends in Phase I because the predicted
concentration in surface water is lower than 0.01 µg/l and the log Dow is lower than 4.5.
Therefore selexipag is not expected to pose a risk for the environment.
2.3.6 Discussion on non-clinical aspects
Upon request, the Applicant has calculated the free concentrations of selexipag/ACT-333679 in in-vitro
functional assays and in in-vitro pharmacokinetic interaction studies and compared these values to the
free therapeutically effective plasma concentrations of both selexipag (0.12 nM) and ACT-333679 (0.28
nM) in order to assess the clinical relevance of the observed findings. The free EC50/IC50 values for
selexipag and ACT-333679 shift to markedly lower values (to the low nanomolar range for selexipag
and to the picomolar range for ACT-333679). As a consequence of these re-calculations, the Applicant
supports the suggestion that there are spare IP receptors, since the IC50/EC50 values for free selexipag
and ACT-333679 are lower compared to the Ki values obtained in binding experiments. The re-
calculated free EC50/IC50 values for selexipag and ACT-333679 correlate with selexipag and ACT-
333679 free peak plasma concentrations of 0.12 nM and 0.28 nM, respectively, at 1600 µg b.i.d. in
humans.
The existence of differences in spare IP receptors together with differences in the degrees of signal
amplification of the IP receptor signaling cascade can explain the different potencies of selexipag/ACT-
333679 in functional assays performed in different in-vitro test systems.
Mice were used in the carcinogenicity studies and rabbits in the reproductive and developmental
toxicity studies performed with selexipag. In order to give an explanation for the findings observed in
mouse carcinogenicity studies and in the rabbit reproductive and developmental toxicity studies, the
Applicant provided results from a new study in which in vitro potencies (EC50 values), as measured by
cAMP accumulation, were determined in recombinant cells expressing similar levels of the mouse,
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rabbit, or human IP receptor. The rabbit and mouse IP-receptors showed 61- and 69-fold lower
potencies for selexipag and 74- and 56-fold lower potencies for ACT-333679, respectively. For any
pharmacological effect mediated via the IP receptor occurring in mouse and rabbit studies, correction
factors for differences in potencies should be applied for the calculation of safety margins. Taking the
correction factors for IP-receptor potency into account, these safety margins diminish to values below
human therapeutic exposures. However, adverse effects in the mouse carcinogenicity study and the
rabbit reproductive toxicology studies are probably not mediated via the IP receptor
Nevertheless, a general statement regarding those differences in IP receptor potency in animals used
for toxicity assessment compared to humans has been included into section 5.3 of the SmPC.
IP prostacyclin receptor agonists have the potential to induce neurogenic pain, and headache, pain,
arthralgia, myalgia, abdominal pain, pain in jaw and pain in extremities are mentioned in the SmPC
under section 4.8 undesirable effects.
Based on the re-calculated free concentrations of selexipag and ACT-333679 in the in-vitro
pharmacokinetic interaction studies, selexipag and its metabolite do not seem to have any relevant
inhibitory potential on CYP P450 enzymes, on transport proteins and on BCRP. However, an induction
of CYP3A4 and CYP2C9 by selexipag in the intestine cannot be excluded. This is therefore mentioned in
the SmPC under section 4.5.
In repeated-dose toxicity studies performed in rats and dogs, platelet count dose-dependently
decreased. The Applicant could not able to provide a mechanistic explanation for this effect observed in
rats. Nevertheless due to the small magnitude of the effect, its reversibility and the absence of effects
on coagulation times or bleeding, the rat finding of decreased platelet counts after administration of
selexipag has no human relevance; furthermore, decreased platelet count has also been observed after
administration of other IP receptor agonists in rat repeated-dose toxicity studies (e.g. for treprostinil).
The decreased platelet counts observed in dogs after administration of selexipag might be IP receptor
mediated because in anaesthetized dogs the infusion of prostacyclin has been demonstrated to
produce splenic dilation that leads via blood pooling to a decrease in circulating blood cell
concentrations. In conclusion, decreased platelet counts observed in repeated-dose toxicity studies
performed in rats and dogs do not seem to be of therapeutic relevance.
Reproductive toxicity of selexipag was studied according to ICH-S5 in the rat and in the rabbit.
Receptor binding studies showed a much lower potency for selexipag and ATC-333679 at the rat and
rabbit IP receptor compared to the human receptor. Therefore, IP mediated effects will probably not
become evident during the reproductive toxicity studies because exposures adapted for IP receptor
potency are usually below human therapeutic exposures. The margins adapted for differences in
receptor potencies are provided in section 4.6 of the SmPC.
In the fertility study performed in rats, estrus cycles were prolonged increasing the time until
copulation in the high dose group. Lower food consumption was observed for those dams, but no
changes in body weights. Therefore, lower maternal body weight was the cause of these findings. The
observation of prolonged oestrus cycle is mentioned in sections 4.6 and 5.3 of the SmPC.
In the embryo-fetal development study in the rabbit, retrocaval ureter was observed with a higher
incidence in the high dose compared to the control group. Historical control data covering different
time frames of the study facility showed that the incidences were within the historical control range.
The same could be shown for the higher incidence of visceral anomalies, in general, observed for the
high dose group of the rat embryotoxicity study. Accordingly, selexipag did not show any teratogenic
effects in the studies on embryo-fetal development with exposure margins, based on total exposures,
of approximately 13-times for selexipag and 46-times for ACT-333678, respectively.
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In the juvenile toxicity study performed in the dog, a delay in sexual maturation in female beagle dogs
was observed. It could be shown that this delay was not due to a direct involvement of prostacyclin in
uterine function, but was rather due to toxicity of selexipag leading to low food consumption and a
massive reduction in body weight gain and low ovary and uterus weights. A delay in the closure of the
femoral and/or tibia epiphyseal growth plate was observed in animals sacrificed at week 39, a finding
which could affect growth of the skeleton. The applicant argues that the distribution of animals with
closed versus open growth plates is still within the normal range. However, effects on the closure of
growth plates were clearly dose dependent. A NOAEL for bone effects was not established. A respective
statement is mentioned in section 5.3 of the SmPC.
2.3.7 Conclusion on non-clinical aspects
From a non-clinical point of view, a Marketing Authorization for selexipag can be granted. Amendments
to sections 4.5, 4.6 and 5.3 of the SmPC have been implemented as required during the assessment.
In conclusion, the SmPC reflects the non clinical finding of relevance for the prescriber.
2.4 Clinical aspects
2.4.1 Introduction
GCP
The Clinical trials were performed in accordance with GCP as claimed by the applicant.
The applicant has provided a statement to the effect that clinical trials conducted outside the
community were carried out in accordance with the ethical standards of Directive 2001/20/EC.
• Tabular overview of clinical studies
Study Reference
Study Title
PS003
An open-label study of the pharmacokinetics, safety and tolerability of a single
microdose of MRE-304 in healthy volunteers
186933
A Phase I study to investigate the absorption, metabolism and excretion of [14C]
NS-304 following oral administration to healthy male volunteers
QGUY/2006/
NS304/
-01
A Phase I study to investigate the safety, tolerability and pharmacokinetics
(including food effect) of single and multiple oral rising doses of NS
-304 and its
interaction with warfarin in healthy male volunteers
NS304/P1/01
Single- and multiple-dose study of NS-304 in healthy adult and elderly male
Japanese volunteers
AC-065-101
A single-center, randomized, placebo-controlled, double-blind, multiple-period,
multiple
-ascending- dose study to assess the safety, tolerability,
pharmacokinetics, and pharmacodynamics of
oral ACT-293987 in healthy male
subjects
AC-065-102
A single-center, assessor-blind, randomized, placebo- and positive-controlled,
parallel group study to evaluate the phototoxic potential, safety, tolerability, and
pharmacokinetics of ACT-293987 in healthy male subjects
AC-065-104
A single-center, open-label, single-dose Phase 1 study to investigate the
pharmacokinetics, to
lerability, and safety of 400 μg selexipag (ACT- 293987) in
subjects with mild, moderate, or severe hepatic impairment compared to healthy
subjects
AC-065-105
Single-center, open-label study to investigate the pharmacokinetics, safety, and
tolerability of
a single oral dose of selexipag in subjects with renal function
impairment
AC-065-106
A single-center, double-blind, randomized, placebo- and positive-controlled,
parallel-group with nested cross-over, multiple-dose, up-titration study of the
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effects of selexipag and its metabolite ACT-333679 on cardiac repolarization in
healthy male and female subjects
AC-065-108
A single-center, open-label, randomized, two- period, two-treatment, crossover
study in healthy male subjects to demonstrate bioequivalence of
1600 μg
selexipag administered as eight tablets of
200 μg (reference drug) or as single tablet of 1600 μg (test drug)
AC-065-109
A single-center, randomized, open-label, 2-treatment, 2-period, cross-over study
to assess the effects of Kaletra® (lopinavir
/ ritonavir) on the pharmacokinetics of
selexipag(ACT-293987) in healthy male subjects
AC-065-110
Single-center, open-label, Phase 1, randomized, two-way crossover, single-dose
to investigate the absolute bioavailability of a single oral dose of selexipa
g in
healthy male subjects.
NS-304/-02
A multicenter, multinational, open-label, single-dose, acute hemodynamic study
followed by a multicenter, multinational, randomized, double
- blind, parallel-
group, placebo
-controlled study to assess the safety, tolerability,
pharmacokinetics, and preliminary efficacy (proof
-of-concept) of ACT-293987
(NS
-
304) in the treatment of pulmonary arterial hypertension in subjects aged 18
years and over
AC-065A201
Clinical Study to assess the efficacy, safety and pharmacokinetics of selexipag in
patients with pulmonary arterial hypertension (PAH)
AC-065B201
An exploratory study to assess the efficacy and Safety of selexipag in patients
with chronic thromboembolic pulmonary hypertension (CTEPH)
AC-065B202
An open-label extension study of selexipag in patients with chronic
thromboembolic pulmonary hypertension (CTEPH) who completed the exploratory
evaluation study (AC-065B201)
AC-065A302
GRIPHON: Prostacyclin (PGI
2
) receptor agonist in pulmonary arterial hypertension
A multicen
ter, double-blind, placebo-controlled Phase 3 study assessing the
efficacy and safety of selexipag (ACT 293987) on morbidity and mortality in
patients with pulmonary arterial hypertension (PAH)
AC-065A303
Open label extension study of AC-065A302
2.4.2 Pharmacokinetics
Selexipag is an orally available, selective non-prostanoid agonist of the prostacyclin (IP) receptor.
Selexipag and its active metabolite, ACT-333679, are active at the IP receptor. ACT-333679 has a 13-
fold higher affinity than selexipag for the human IP receptor. It is present at 3- to 4-fold higher levels
than the parent drug at steady-state in humans. ACT-333679 is the major contributor to the efficacy of
selexipag.
In total, 12 studies were preformed that were classified as PK-studies. In addition, PK was measured in
PD and phase III studies.
Methods
Bioanalytical methods studies (high performance liquid chromatography coupled to tandem mass
spectrometry [LC-MS/MS]) enabled measurement of selexipag and ACT-333679 concentrations in
human plasma samples. These methods were sensitive, precise, and linear in the concentration range
of 0.01–20.00 ng/mL for both selexipag and ACT-333679. Five method validation reports were
provided. The two most frequently used methods were cross validated. Standard PK parameters and
statistical analyses were used.
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Absorption
An intravenous (i.v.) formulation of selexipag, has been developed and an absolute bioavailability
study has been conducted (AC-065-110). The geometric mean (90% CI) absolute bioavailability
calculated for selexipag is 0.49 (0.43, 0.57).
Relative bioavailability after oral administration has been properly characterized. PK results with
solution (study PS003) and tablet (study QGUY/2006/NS-304/01) were found to be comparable.
The Applicant has not investigated the absorption site of selexipag. However, based on surface-to-
volume characteristics and pH (around 8), most of the absorption of selexipag (freely soluble at pH 8)
is anticipated to occur in the duodenum.
Following single-dose administration (100 to 800 µg), the PK profile of selexipag is characterized by
rapid absorption with Cmax achieved within 1 h after drug administration and a t1/2 of approximately
0.8–2.5 h. The active metabolite, ACT 333679, is formed rapidly and eliminated with a t1/2 of
approximately 6–13 h.
An in vitro study was conducted to compare the dissolution profiles of 400, 600, 800, 1000, 1200,
1400, and 1600 μg film-coated tablets with that of the dose strength of 200 μg, in dissolution media of
four different pH values: 1.2, 4.5, 5.5, and 6.8. When the dissolution profile of multiple tablets of the
200 µg dose was compared to that of a single tablet of higher strengths (e.g., 2 × 200 µg tablets vs 1
× 400 µg tablet), the f2 value was above 50 for all dose strengths and at all dissolution pH values. In
addition, bioequivalence between 1 tablet of 1600 μg and 8 tablets of 200 μg selexipag was
demonstrated in study AC-065-108 (figure 3).
Linear scale Semilogarithmic scale
Figure 3: Selexipag arithmetic mean (± SD) plasma concentration-time profiles of selexipag over 12 h
in healthy subjects (n = 65) at steady-state (Day 23) after treatment with 1600 µg selexipag in
Treatment A (8 × 200 μg tablets; black) and Treatment B (1 × 1600 μg tablet; red)
In the presence of food, median time to reach maximum plasma concentration (tmax) of both selexipag
and ACT-333679 was delayed (2.75 and 4.0 h, respectively) compared to in the absence of food (1.0
and 2.5 h, respectively). Cmax of selexipag decreased by 35% whereas the area under the plasma
concentration-time curve from 0 to infinity (AUC0-∞) numerically increased by approximately 10% in
the presence of food. Cmax and AUC0-∞ of ACT-333679 decreased by 48 and 27%, respectively, in the
presence of food (figure 4).
Uptravi (Selexipag) Assessment Report
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Linear scale Semilogarithmic scale
Figure 4: Mean (+SD) plasma concentration-time profiles of selexipag and ACT-333679 in healthy
male subjects following single oral doses of 400 μg selexipag in the fasted (n = 11) and fed state (n =
12) (study QGUY/2006/NS304/-01 Part B)
Distribution
In vitro experiments showed that selexipag and ACT-333679 are highly bound to plasma proteins (>
99%), which was confirmed in phase 1 studies. Partitioning studies with selexipag and ACT-333679
indicated little or no binding of either compound to blood cells.
The geometric mean (95% CI) volume of distribution at steady-state (Vss) of selexipag is 11.73 L
(95% CI 10.55, 13.04; results from study AC-065-110), which is comparable to the volume of
extracellular fluid (plasma plus interstitial fluid, around 15 L). This indicates that the distribution is
limited mainly to the extracellular fluid and that selexipag does not accumulate in tissues.
Preclinical data indicate that selexipag and ACT-333679 permeate well through cell membranes and
tissue distribution is mainly driven by passive diffusion.
Metabolism
Based on nonclinical findings, selexipag undergoes enzymatic hydrolysis by CES1 in the liver, to yield
the active metabolite ACT-333679. Investigations in human liver microsomes (HLM) and with
recombinant cytochrome P450 (CYP) enzymes indicate that the UGT enzymes UGT1A3 and UGT2B7
contribute 42% to the metabolism of ACT-333679, while CYP2C8 and CYP3A4 contribute to 46% and
12%, respectively.
Elimination
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In a human ADME study with 14C selexipag (study 186933), approximately 93% of radioactive drug
material was eliminated in faeces at 168 h post-dose, none in the form of unchanged selexipag. A
number of metabolites, including ACT-333679 (approximately 9–23%), were recovered in the faeces,
indicating extensive metabolism of selexipag prior to biliary excretion.
ACT-333679 has the potential to undergo enterohepatic recirculation, but its extent is limited by the
small amount of ACT-333679 present in bile.
Renal excretion was shown to be a minor route of elimination.
Dose proportionality and time dependency
Selexipag and ACT-333679 showed a dose-proportional increase in AUC and Cmax after multiple-dose
administration in healthy subjects. After multiple dosing (400 to 1800 μg b.i.d), steady-state
conditions of selexipag and ACT-333679 were achieved within 3 days. Morning trough concentrations
of both selexipag and ACT-333679 were somewhat higher than evening trough concentrations, which
is thought to be due to the increased blood circulation and resulting increased metabolism during the
day compared to the night, affecting the clearance of selexipag and ACT-333679. No accumulation of
selexipag or ACT-333679 was observed.
Figure 5: Arithmetic mean plasma concentration-time profiles of selexipag (ACT-293987) and ACT-
333679 after multiple (Day 3) oral administrations of different dose levels of ACT-293987 in healthy
male subjects (study AC-065-101)
Intra- and inter-individual variability
The intra-subject CVs of selexipag and ACT-333679 were about 25 % for AUCτ and Cmax,ss. The inter-
subject CVs of selexipag and ACT-333679 were about 40 % for AUCτ and Cmax,ss.
Pharmacokinetics in target population
Exposure to selexipag and ACT 333679 were estimated to be 30% and 20%, respectively, higher in
patients with PAH or CTEPH compared with healthy subjects.
Special populations
Gender, race and age are of minor importance for selexipag and ACT-333679 pharmacokinetics.
Body weight was identified as significant covariate for the volume of distribution as well as for drug
exposure and clearance of selexipag and ACT-333679.
In the PK Study AC-065-105, the plasma concentrations of selexipag (~1.7-fold) and ACT-333679
(~1.5-fold) were higher in subjects with severe renal function impairment compared to healthy
subjects (patients with mild or moderate renal impairment were not investigated). On the other hand,
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in the confirmatory study AC-065A302 065A302/GRIPHON, CrCl was not identified as a significant
covariate towards the PK of selexipag and ACT-333679.
In PK study AC-065-104, the exposure to selexipag generally increased with the severity of hepatic
impairment. When compared to healthy subjects, the plasma concentrations of selexipag in subjects
with mild hepatic impairment increased about 2-fold. Plasma concentrations of ACT-333679 and
derived PK parameters were comparable with those for healthy subjects, except for t1/2 (6.5 versus
12.6 h).
Plasma selexipag concentrations were markedly higher in subjects with moderate hepatic impairment
(more than 4-fold increase in AUC0-∞). Median tmax (6.0 h) and mean t1/2 (15.9 h) of ACT-333679
were longer in subjects with moderate hepatic impairment compared to healthy subjects (4.0 h and
12.6 h, respectively). Overall, this resulted in a 2.2-fold increase in exposure (AUC0-∞) to ACT-333679
in subjects with moderate hepatic impairment compared to healthy subjects. Only 2 subjects with
severe hepatic impairment receiving a lower dose (200 vs 400 μg) were included and therefore,
conclusions in this special population are limited. In study AC-065A302/GRIPHON, ALT and AST at
baseline were not identified as significant covariates towards the PK of selexipag and ACT-333679.
However, total bilirubin at baseline was identified as significant covariate for selexipag clearance.
The list of studies performed in elderly is detailed below. Age is of minor importance for selexipag and
ACT-333679 pharmacokinetics.
Table 2: List of studies performed in elderly with breakdown on number of pstients per age group.
eCTD Module
Age 65–74
number / total number (all
ages)
Age 75–84
number / total number
(all ages)
Age 85+
number / total number
(all ages)
Efficacy and Safety Studies1:
NS-304-02
AC-065A201
AC-065A302
AC-065B201
218/1270
11/43
4/37
193/1156
10/34
20/1270
3/43
0/37
13/1156
4/34
0/1270
0/43
0/37
0/1156
0/34
Human PK Studies:
PS003
186933
QGUY/2006/NS304/-01
NS-304P01/1
AC-065-104
AC-065-105
AC-065-109
25/233
0/5
0/6
0/96
16/64
1/26
8/16
0/20
2/233
0/5
0/6
0/96
0/64
0/26
2/16
0/20
0/233
0/5
0/6
0/96
0/64
0/26
0/16
0/20
Human PD Studies:
AC-065-101
AC-065-102
AC-065-106
0/227
0/16
0/52
0/159
0/227
0/16
0/52
0/159
0/227
0/16
0/52
0/159
Biopharmaceutical Studies:
AC-065-108
0/80
0/80
0/80
0/80
0/80
0/80
Controlled trials:
NS-304-02
AC-065A302
AC-065B201
214/1233
11/43
193/1156
10/34
20/1233
3/43
13/1156
4/34
0/1233
0/43
0/1156
0/34
Non controlled trials:
AC-065A201
4/37
4/37
0/37
0/37
0/37
0/37
1For AC-065A302, 4 randomized patients (in the placebo group) are included in the total number of patients although they were
not treated. Open-label extension studies are not included as patients would be counted more than once.
Paediatric population
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To date, no patients younger than 18 years have been treated with selexipag. The Applicant does not
apply for use of selexipag in children or adolescents.
Interactions
Based on in vitro studies, the metabolism of selexipag was mostly driven by initial hydrolysis to the
major metabolite ACT-333679, catalysed by hepatic CES1 in humans. No clinically relevant inhibition of
CES1 by medicinal products has been reported.
The transformation of selexipag to other metabolites was catalysed by CYP2C8, CYP3A4, and CYP1A2.
The UGT enzymes UGT1A3 and UGT2B7 contribute 42% to the metabolism of ACT-333679, while
CYP2C8 and CYP3A4 contribute to 46% and 12%, respectively.
Selexipag and its active metabolite affecting the exposure of the patient to other drugs
The potential of selexipag and its metabolite, ACT-333679, to elicit CYP-mediated drug-drug-
interactions (DDIs) was studied in vitro using human hepatic microsomes and CYP isoform-specific
marker transformations. The lowest derived half maximal inhibitory concentration (IC50) was 3.6 µM
(selexipag on CYP2C8). The mean peak plasma concentrations of selexipag and ACT-333679 in human
were 19.8 ng/mL and 28.7 ng/mL, i.e., about 0.04 μM and 0.07 μM, respectively. Although both
compounds have shown an inhibitory potential against CYP2C8 and CYP2C9 activity in vitro, their
potential for CYP-mediated DDIs appears negligible in light of the low unbound concentration of both
selexipag and its metabolite, ACT-333679, in human plasma. However, assuming a luminal selexipag
concentration of 1.3 µM and a free selexipag concentration in enterocytes of 8 nM, clinically relevant
induction of CYP3A4 and CYP2C9 in the gut cannot be excluded.
Drugs affecting the exposure of the patient to selexipag and its active metabolite
Study QGUY/2006/NS304/-01 Part D was performed to investigate the potential PK (and PD)
interactions between selexipag and warfarin in healthy male subjects. The geometric mean ratios
(selexipag + warfarin vs selexipag alone) and their 90% CIs for AUCτ of selexipag (400 µg) and for
AUCτ and Cmax of ACT-333679 were within the bioequivalence range of 0.8 to 1.25. The lower
boundary of the 90% CI for Cmax was 0.77 (geometric mean ratio 0.94). Visual inspection of mean
morning trough plasma concentrations of selexipag and ACT-333679 before (on Days 5–6) and after
single dose administration of warfarin (measured on Days 9–11) showed that co-administration of
warfarin on Day 8 had minor effect on the trough concentrations of selexipag and ACT-333679 at
steady-state.
In study AC-065-109 (a randomized, two-treatment, two-period crossover study), the effects of
multiple doses of lopinavir/ritonavir (Kaletra) on the PK of selexipag (administered as a single 400 μg
dose) and ACT-333679 were evaluated. The study was performed as selexipag and ACT-333679 have
been identified in vitro as substrates of OATP transporters (OATP1B1 and OATP1B3) and lopinavir and
ritonavir are inhibitors of these transporters. In addition, lopinavir/ritonavir is known to be a strong
inhibitor of CYP3A4 and an inhibitor of P-gp. Plasma concentrations of selexipag were higher (almost 2-
fold) in the presence of lopinavir/ritonavir than when it was administered alone. For ACT-333679, in
the presence of lopinavir/ritonavir, Cmax and AUC0-∞ were 1.3- and 1.1-fold higher, respectively. The
results are adequately described in the SmPC.
Of note, no clinical DDI study was performed with a strong inhibitor of CYP2C8 (gemfibrozil), an
inhibitor of UGTs (valproic acid), or an inducer of CYP2C8 and UGTs (rifampicin).
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2.4.3 Pharmacodynamics
The clinical pharmacology data come from studies in healthy volunteers. The effect of selexipag and its
metabolite on platelet aggregation, coagulation parameters, bone metabolism, cardiac repolarisation,
and in-vivo drug-drug interactions was evaluated. Additionally, the phototoxic potential of selexipag
was investigated.
Prostacyclin (PGI2) is a member of the prostaglandin family, which are endogenous, oxygenated fatty
acid metabolites deriving from arachidonic acid. A dysregulation of the PGI2 pathway has been
observed in patients with pulmonary arterial hypertension and in animal models of hypoxic pulmonary
hypertension. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation. For example,
the binding of PGI2 to the IP receptor, a G-protein coupled receptor on the surface of vascular smooth
muscle cells, triggers an increase of intracellular cyclic adenosine monophosphate (cAMP), which leads
to relaxation of vascular smooth muscle cells, and vasodilation of the pulmonary arteries. In this
manner prostacyclin can counteract the vasoconstrictor activity of thromboxane and endothelin.
Selexipag acts as a selective, orally bioavailable, non-prostanoid IP receptor agonist. Selexipag
undergoes an enzymatic hydrolysis of the sulfonamide by carboxylesterase 1 (CES1) in the liver, to
yield the active metabolite ACT-333679. ACT-333679 has a 13-fold higher affinity than selexipag for
the human IP receptor and it is at least 16-fold more potent than selexipag in cellular systems. In vitro
experiments measuring cellular shape change using human pulmonary arterial smooth muscle cells
showed that ACT-333679 is 37-fold more potent than selexipag in activating the human IP receptor.
ACT-333679 is considered to be the major contributor to the efficacy of selexipag.
Primary and secondary pharmacology
Effects of selexipag on platelet aggregation, bleeding, and bone metabolism; identification
of maximal tolerated dose
The relationship between plasma concentration and pharmacodynamic parameters of platelet
aggregation and coagulation (ex vivo testing) was investigated in 16 healthy subjects in study AC-065-
101 (placebo-controlled, multiple ascending dose study, 12 subjects on selexipag, 4 on placebo).
Results after multiple-dose administrations of either selexipag or placebo indicated a high level of
variability and no consistent differences in platelet aggregation test related PD parameters across the
doses tested were observed. There was no obvious drug- or dose-dependent pattern. Mean % vWF
measured on each third day after dose escalation was comparable between selexipag and placebo,
albeit there was a trend for a decrease of vWF with selexipag, the vWF values remained above the
lower limit of the normal range. Mean concentrations of the coagulation markers sTM and P-selectin
after treatment with selexipag were not different from placebo. No changes from baseline were
observed.
Increased bone ossification was reported in nonclinical studies in the Beagle dog with selexipag
(studies T08/286 and T08/290). In humans no differences were observed between mean
concentrations of bone formation PD markers (sOC, P1NP) or bone resorption markers (CTx, NTx;
study AC-065-101) after treatment with selexipag or placebo.
The subjects were exposed to dose levels of Selexipag up to 1600 µg bid. The dose level of 1800 µg
selexipag bid was less well tolerated due to an increase in moderate AEs (headache, myalgia, and
nausea) that required concomitant medication. The maximum tolerated dose was determined as 1600
µg bid of selexipag. This dose was selected for further phase 3 testing.
Effects of selexipag on cardiac repolarisation: study AC-065-106 (thorough QT study)
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The aim of this study was to demonstrate that selexipag and its metabolite do not have an effect on
cardiac repolarisation measured by the QT interval at steady-state at 2 oral dose levels (800 and
1600µg bid) in 159 healthy male and female subjects. This was a double-blind, placebo controlled,
parallel group with nested cross-over, multiple-dose, up-titration study with a positive control (single
dose of moxifloxacin). Baseline characteristics were generally comparable between the selexipag group
(treatment A) and the moxifloxacin group (treatment B).
Selexipag administration was associated with a mild increase in heart rate, with the largest placebo-
corrected change from baseline heart rate reaching 6–7 bpm at 1.5 to 3 h after dosing with 800 μg
selexipag and 9–10 bpm at the same time points after 1600 μg selexipag. There was no effect on
mean blood pressure. Selexipag did not show an effect on cardiac repolarisation. Change from baseline
QT interval corrected using the individualised formula QTcI (ΔQTcI) was small at all timepoints and the
placebo-corrected ΔQTcI (ΔΔQTcI) did not exceed 1.4 ms (UB of 90% CI 3.9 ms) on selexipag 800µg
and -0.7 ms (UB of 90% CI 2.1 ms) on 1600µg selexipag. There were no subjects with QTcI exceeding
480ms or ΔQTcI>30 ms on selexipag. Mean ΔΔQTcI peak effect for 400 mg moxifloxacin was 7.5 ms
with a LB of the 90%CI of 4.8 msec. The LB of the 90% CI did not exceed 5.0 ms (the threshold
indicated by the ICH E14 guidance) at any of the post-dose timepoints.
In this study no adverse experiences of Torsades de Pointes, sudden death, ventricular tachycardia,
ventricular fibrillation or flutter, or seizures were reported.
Phototoxic potential of selexipag
In-vitro data suggested that selexipag and its active metabolite were potentially phototoxic. The
photosensitizing potential of selexipag (800 and 1200 μg bid) was investigated in 52 healthy subjects,
compared to placebo and ciprofloxacin (positive control; study AC-065-102). The photosensitizing
potential of selexipag was assessed by evaluating the subjectʼs cutaneous responses to UV irradiation
(UV-A at 320–400 nm and UV-B at 290-320 nm) prior to and during the treatment period. Subjects
were considered photosensitive if the Phototoxic Index (PI), defined as the ratio of baseline minimal
erythema dose (MED) to post-dose MED (24 h after UV-irradiation) was greater than 1.66 for any
waveband. The mean PI was below 1.66 for UV-A in all treatment groups, while it was greater than
1.66 for UV-B in each treatment group. No statistically significant differences in UV-A or UV-B PI
between either selexipag dose and placebo or ciprofloxacin were observed. Overall, for UV-A and UV-B,
administration of 800 μg and 1200 μg bid selexipag was not associated with clinically relevant
phototoxic potential when compared to placebo or ciprofloxacin.
Substance P
As both selexipag and its metabolite are IP receptor agonists, substance P levels could increase in
selexipag treated subjects and could increase pain perception. No effect of selexipag was observed on
plasma substance P concentrations (study AC-065-102).
Relationship between plasma concentration and effect
The PK/ PD relationship between selexipag/ metabolite plasma levels and selected clinical safety and
efficacy endpoints was evaluated using a population approach using data from the GRIPHON study AC-
065A302. The main finding was a small but statistically significant increase in the 6MWT with
increasing exposure, from 369 m with no exposure to 392 m with high exposure.
One phase 2 study (NS-304/02) investigated the relationship between hemodynamic parameters and
the dose after individual up-titration. The primary endpoint was pulmonary vascular resistance (PVR).
The study included 43 patients with PAH which were randomized in a 3:1 fashion to selexipag or
placebo. The hemodynamic efficacy of selexipag, individually up-titrated to a maximum dose of 800 μg
bid, versus placebo was evaluated at week 17. At this time, PVR (geometric mean and 95% CI) was
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80.7% (72.8, 89.6; n = 29) and 115.9% (106.5, 126.1; n = 6) of the baseline values in the selexipag
and placebo groups, respectively. The percent decrease (vs placebo) in geometric mean PVR of 30.3%
on selexipag treatment was statistically significant (95% CI: -44.7, -12.2; p = 0.0045, Wilcoxon rank-
sum test). There was no clear relationship between change in PVR and the patient`s optimized dose in
this study. The PK data indicated that the mean exposure to selexipag and its metabolite at week 17
were in a similar range across all dose groups.
In-vivo interaction studies
In-vivo interaction studies were performed with warfarin and with lopinavir/ritonavir.
Selexipag given as multiple doses of 400 μg bid had no effect on the exposure to R-warfarin (CYP3A4
substrate) or S-warfarin (CYP2C9 substrate) after administration of a single dose of 20 mg warfarin
(study NS304/-01). The pharmacodynamic effect of warfarin on the International Normalized Ratio was
not affected by selexipag. The PK of selexipag and its active metabolite were not affected by warfarin.
Genetic differences in PD response
No DNA samples were collected during clinical development of selexipag.
2.4.4 Discussion on clinical pharmacology
Pharmacokinetics
Methods
Analytical methods used for determination of selexipag and ACT-333679 concentrations in human
plasma samples are considered suitable and properly validated.
Absorption
An absolute bioavailability study has been conducted (AC-065-110) and indicated an absolute
bioavailability for selexipag of 0.49 (0.43, 0.57). However, the results for the metabolite ACT-333679
suggest selexipag to be subject to a first pass effect leading to underestimation of the bioavailability.
The AUC-value for ACT-333679 after a single oral dose of 400 μg selexipag was approximately 2.55
times higher compared with 200 μg selexipag i.v. indicating an almost complete absorption of
selexipag.
Relative bioavailability after oral administration has been properly characterized. PK results with
solution (study PS003) and tablet (study QGUY/2006/NS-304/01) were found to be comparable.
The Applicant has not investigated the absorption site of selexipag. However, based on surface-to-
volume characteristics and pH (around 8), most of the absorption of selexipag (freely soluble at pH 8)
is anticipated to occur in the duodenum. In study AC-065A302/GRIPHON, 142 (28%) out of the 510
patients included in the population PK (PopPK) analysis received at least one gastric pH-modifying
drug. The results suggest no relevant difference with respect to exposure or absorption between
patients receiving compared to those not receiving gastric pH-modifying drugs.
Selexipag and ACT-333679 showed a dose-proportional increase in AUC and Cmax after multiple-dose
administration in healthy subjects. Steady state conditions were achieved within 3 days.
Bioequivalence between 1 tablet of 1600 μg and 8 tablets of 200 μg selexipag has been demonstrated.
A biowaiver for the intermediate dose strengths (400, 600, 800, 1000, 1200, and 1400 μg film-coated
tablets) is considered justified because the manufacturing process is the same, the qualitative and
quantitative composition is the same (except for the filler D-mannitol which compensates for
differences in active substance) and the comparison of dissolution profiles gave f2 values above 50 for
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all dose strengths and dissolution pH tested. Overall, bioequivalence between equimolar doses of
different dose strengths can be assumed.
The influence of food on the pharmacokinetics of selexipag is characterised properly. Due to improved
tolerability and to avoid changes in exposure when switching from fasting to fed intake or vice versa, it
is recommended to take selexipag in the fed state only.
Distribution
Except for protein binding and whole blood / plasma distribution, only few data are available on
distribution. The volume of distribution of selexipag at steady state is 11.7 L. Taken together, the data
indicate that drug distribution is most prominent in the extracellular fluid and that selexipag does not
accumulate in tissues outside the plasma and interstitial fluid.
Metabolism / Elimination
Selexipag undergoes enzymatic hydrolysis by CES1 in the liver to yield the active metabolite ACT-
333679. The UGT enzymes UGT1A3 and UGT2B7 contribute 42% to the metabolism of ACT-333679,
while CYP2C8 and CYP3A4 contribute to 46% and 12%, respectively.
Special populations
Gender, race and age are of minor importance for selexipag and ACT-333679 pharmacokinetics.
Body weight was identified as significant covariate for selexipag and ACT-333679 exposure. However,
effect on ACT-333679, the major contributor to the efficacy of selexipag, is limited and since selexipag
dosage will be based on individual tolerability, PK-dependency of weight is not considered an issue.
Pharmacokinetics in patients with renal or hepatic impairment is characterised properly. The applicant
suggests warnings in the SmPC that, in patients with moderate hepatic impairment the starting dose of
200 micrograms once daily (instead of twice daily) and increase at weekly intervals by increments of
200 micrograms given once daily (instead of twice daily) is recommended. In patients with severe
hepatic impairment, selexipag should not be used.
In patients undergoing dialysis, Uptravi should not be used. For patients with severe renal impairment,
caution should be excerciced during dose titration.
No adjustment in dose regimen is needed in patients with mild or moderate renal impairment and in
patients with mild hepatic impairment.
The respective wording in the proposed SmPC is in agreement with the results of the studies and is
acceptable.
Interactions
Effects of selexipag and ACT-333679 on enzymes and transporters in the plasma and accordingly
possible PK interaction with other drugs are considered negligible. However, assuming a luminal
selexipag concentration of 1.3 µM and a free selexipag concentration in enterocytes of 8 nM, clinically
relevant induction of CYP3A4 and CYP2C9 in the gut cannot be excluded. To address this point the
applicant will conduct a clinical drug-drug interaction (DDI) study with midazolam as a post-approval
commitment.
No effect of warfarin on the PK of selexipag or ACT-333679 was observed. The effect of
lopinavir/ritonavir is considered clinically not relevant because, although plasma concentrations of
selexipag increased almost 2-fold in the presence of lopinavir/ritonavir, the increase in exposure (1.1-
fold) and Cmax (1.3-fold) of the active metabolite (which is the major contributor to efficacy) was small.
The lopinavir/ritonavir interaction study suggests minor importance of OATP1B1, OATP1B3, CYP3A4
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and P-gp, however simultaneous inhibition of several compounds limit the interpretation to some
extent as effects may counterbalance each other.
No data were provided in respect to a possible influence of transporter / enzyme inhibition or induction
on the PK of selexipag or ACT-333679. This appears most important in respect to CYP2C8. A warning
in respect to the combination of selexipag with CYP2C8, UGT1A3, and UGT2B7 modulators with an
explicit listing of the drugs known to modulate these enzymes is included in the SmPC. The applicant is
planning to undertake, as a post-approval commitment, a clinical DDI study with gemfibrozil, a strong
inhibitor of CYP2C8. The extent of increased drug elimination by induction of CYP2C8 cannot be
predicted and might result in a relevant loss of efficacy. To address this point, the applicant is planning
to conduct a clinical DDI study with rifampicin as a post-approval commitment in addition to the DDI
study with gemfibrozil. If it cannot be concluded that CYP2C8 is the major enzyme involved in the
elimination of selexipag further studies may be needed to characterize the elimination in vivo.
Pharmacodynamics
The effect of selexipag and its metabolite on platelet aggregation, coagulation parameters, bone
metabolism, cardiac repolarisation, and interaction with concomitantly administered drugs was
investigated in healthy volunteers. In addition, the potential of selexipag to cause phototoxic reactions
was investigated.
Prostacyclin is a potent inhibitor of platelet aggregation. Selexipag inhibited platelet aggregation
induced by ADP in platelet-rich plasma from humans and monkeys with IC50 values of 5.5 and 3.4 μM,
respectively (for details please refer to Nonclinical section). In study AC-065-101 pharmacodynamic
Platelet Aggregation Test parameters (Emax, Etrough, AUE0-12, and tmax) after multiple-dose
administration of either ACT-293987 or placebo twice daily (b.i.d) indicated a high level of variability
presumably due to the limited number of subjects. There was no obvious drug- or dose-dependent
pattern. In vitro data indicated that the mean maximal and trough plasma ACT-333679 concentrations
in humans at 1600 μg b.i.d. are 3- and 16-fold lower than the IC50 of ADP-induced platelet
aggregation, respectively; at these concentrations, platelet aggregation is inhibited by 1-15%. Overall,
at therapeutic plasma levels an inhibitory effect on platelet aggregation is considered unlikely.
Because prostaglandin I2 receptors play a role in bone remodelling and because increased ossification
was reported in a toxicity study in dogs, the effect of selexipag on bone formation markers and bone
resorption markers was investigated. No differences to placebo were observed for any marker.
However, in view of the low subject number and high variability a firm conclusion of a neutral effect of
selexipag on bone metabolism cannot be drawn.
Selexipag did not affect cardiac repolarisation based on the thorough QT study (AC-065-106)
conducted in accordance with Guideline ICH E14.
Selexipag was not associated with a clinically relevant phototoxic potential (study AC-065-102).
Selexipag seems not to increase Substance P which is involved in pain perception.
In-vivo interaction studies in healthy subjects were performed with warfarin and lopinavir/ritonavir.
Selexipag (400 µg twice a day) did not alter the exposure to S-warfarin (CYP2C9 substrate) or R-
warfarin (CYP3A4 substrate). Selexipag did not influence the pharmacodynamic effect of warfarin on
the international normalized ratio. The pharmacokinetics of selexipag and its active metabolite are not
affected by warfarin. Thus, selexipag can be used in combination with warfarin without dose
adjustment. Based on similar metabolism, this conclusion is considered valid also for other vitamin K
antagonists, such as phenprocoumon and acenocoumarol.
Potential drug-drug interactions between PAH co-medication (ERA and/or PDE inhibitor) and selexipag
and its active metabolite were investigated in the phase 3 program by PopPK/PD analyses. PAH co-
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medications (ERAs, PDE-5 inhibitors, and both) did not affect the PK of selexipag but statistically
significantly increased the elimination rate constant of ACT-333679. The concomitant use of both an
ERA and a PDE-5 inhibitor was predicted to result in a 30% lower exposure to ACT-333679 (please
refer to section on PopPK/PD).
The SmPC reflects the findings of the PopPK analysis. However, the clinical relevance of the lower
exposure determined in the PopPK analysis may be limited in light of the high intra-individual (87% for
selexipag, 70% for the metabolite) and inter-individual variability (30%) found in the PopPK analysis.
The relationship between plasma concentration and effect was explored within the clinical development
program (study NS-304/02) and by population PK/PD modelling using data from the phase 3 study.
The population PK/PD analysis found a small increase (by 23m) in efficacy (6MWT) with increasing
dose. A proof-of-concept study NS-304/02 supported the efficacy of selexipag in patients with PAH
over the proposed dose range of 200 µg to 800 µg bid. PVR was significantly reduced by about 30%
compared to placebo. A dose-proportional effect on PVR could not be found in this study, which is likely
due to the low patient numbers studied and high variability.
Based on the data available, no conclusion on a positive relationship between dose and effect can be
drawn. This is considered of limited clinical importance since an individual up-titration regimen based
on individual tolerability is proposed for selexipag. Gradual up-titration to the individual patient`s
tolerated dose is the general accepted regimen for prostaglandin receptor agonists. Based on
tolerability in healthy male subjects (study ACT-065-101), 1600µg bid was selected as the maximal
tolerated dose for further phase 3 testing.
2.4.5 Conclusions on clinical pharmacology
Pharmacokinetics
In general, the evaluation of pharmacokinetics is considered appropriate.
Limited data were provided in respect to a possible influence of transporter / enzyme inhibition or
induction on the PK of selexipag or ACT-333679. This appears most important in respect to CYP2C8. In
addition a clinically relevant induction of CYP3A4 and CYP2C9 in the gut by selexipag cannot be
excluded. The applicant has committed to conduct post-marketing studies to address these issues,
which is considered acceptable.
Pharmacodynamics
Based on the clinical pharmacology data selexipag does not affect cardiac repolarisation. Selexipag has
no phototoxic potential.
No relevant in-vivo drug-drug interactions were found. No clear dose-response relationship was
demonstrated. However, this is considered without clinical relevance since an individual dose up-
titration according to tolerability is proposed. The dose range selected for the phase 3 study is
considered justified based on the pharmacology data.
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2.5 Clinical efficacy
2.5.1 Dose response studies
Summary of main efficacy results
The clinical phase 2 and 3 studies relevant for dose finding, efficacy and safety are summarised in
table 1.
The application also contains information from Phase 2 studies conducted in other indications, i.e., a
controlled study and its open-label extension in patients with chronic thromboembolic pulmonary
hypertension (CTEPH) and an ongoing controlled study in patients with arteriosclerosis obliterans
(Table 2).
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Dose-response studies
Doses in the range of 200 – 1600 µg b.i.d. were administered in the pivotal study (GRIPHON study)As
with other IP receptor agonists, dosing of selexipag aimed at achieving the maximum individually
tolerated dose for maintenance treatment. In the pivotal GRIPHON study, this was achieved through a
12-week up-titration program, allowing a highest dose of 1600 μg b.i.d. (the dose defined as the
maximum well-tolerated dose in healthy subjects).
The selection of the dose regimen and titration scheme used in the phase 3 study was based mainly on
data from the PK/PD study NS-304/02. Phase I studies indicated that single doses of selexipag 100,
200, and 400 μg given after overnight fasting were well tolerated. Single doses of selexipag 600 and
800 μg led to adverse events like headache, nausea, dizziness, and vomiting. Multiple doses of
selexipag 200, 400, and 400/600 μg twice daily (b.i.d.) were better tolerated. Improved tolerability
after repeated dosing was suggested by the poor tolerability of a single 600-µg dose, whereas 600 μg
b.i.d. was better tolerated when it followed administration of 400 µg b.i.d. during multiple dosing.
A b.i.d. application was selected in order to attain an acceptable exposure (AUC) of both the parent
compound and the active metabolite ACT-333679 over the course of 24 h. In selexipag Phase 1 studies
AC-065-101, AC-065-106 and AC-065-108 in which “forced” up-titrations were performed (as opposed
to titration-by-tolerability), a trend for an increase in treatment emergent AEs typical for prostacyclin
therapy was observed with increasing dose. This was also accompanied by a premature discontinuation
rate (ranging between 19–38%) that was higher than that observed in Phase 2/3 studies. The use of
weekly intervals between titration steps in study AC-065A302 was based on practical considerations.
The starting dose of 200 μg b.i.d. in the pivotal study AC-065A302 was based on safety and tolerability
data from study QGUY/2006/NS304/-01, a comparable tolerability profile of multiple doses of both 200
μg and 400 μg b.i.d. was demonstrated on initiation with the lower dose to account for potential inter-
individual differences. Titration steps of 200 μg b.i.d. were introduced based on the understanding that
the first up-titration step to 400 μg b.i.d. would result in a dose that had shown acceptable tolerability
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as a starting dose in study QGUY/2006/NS304/-01. The highest allowed dose in AC-065A302 of 1600
μg b.i.d. was based on the observation from the Phase 1 study AC-065-101, in which the incidence of
AEs of moderate severity requiring administration of concomitant medication was greater on the
highest tested dose of 1800 μg b.i.d. compared to the 1600 μg b.i.d. and lower doses. No severe AEs
were reported on any highest dose. The concept of gradual dose uptitration according to individual
patient tolerability was further supported by data from studies in Japanese patients with PAH Dana
class 1 (AC-065A201, individual dose titration from 200 to 1600 μg b.i.d.) and in patients with CTEPH
(AC-065B202, individual dose titration from 100 to 800 μg b.i.d.) Albeit no clear dose relation for PVR
was seen in study AC-065A201, efficacy on PVR appeared to be higher at the highest maintenance
doses (1400 and 1600 µg bid).
The approach of an individual dose titration guided by tolerability is based on an assumption of a
relationship between maximally tolerated and efficacious doses in the individual patient. As discussed
below, the assumption seemed to be supported by the result for the primary efficacy endpoint in the
pivotal GRIPHON trial. There was no correlation between maintenance dose and primary efficacy
outcome.
Study NS-304/-02 was important for the selection of the doses used in phase 3. It was a
multicenter, multinational, prospective, Phase 2a study of ACT-293987 treatment in PAH patients
conducted in two periods: an open-label, single-dose acute period evaluating the effect of the drug on
the hemodynamic parameters, followed by a randomized, double-blind, parallel-group, placebo-
controlled 21-week treatment period investigating change in PVR, 6 MWT, Borg dysponea scale and
other parameters. In the double blind treatment patients were uptitrated from 200 µg b.i.d. to a
maximally tolerated individual dose but not above 800 µg b.i.d. 43 patients were enrolled and
randomized 3:1 selexipag vs. placebo. The interpretation of the data is hampered by the low number
of patients included and by the exclusion of 8 patients from the per-protocol set, leaving only 6
patients in the placebo group. There was an effect on PVR, on 6- MWT, a small effect on other
haemodynamic parameters and on plasma NT pro-BNP concentrations. However, no conclusions can be
drawn, whether there was a dose relation or not. No treatment effects were seen on NYHA functional
class and Borg dyspnea score, and echocardiographic parameters. For 6-MWT there was even a
negative result in patients receiving the lowest maintenance dose of 200 µg b.i.d. (n=4). This result
was consistent with the result in the pivotal GRIPHON study. In GRIPHON, patients on a maximally
tolerated dose <500 µg bid also had a negative effect on the 26 week 6 MWT as compared to placebo
(see below).
The applicant has discussed the limitations of the assessment of the 6 MWD in relation to attained
individual maintenance dose. In GRIPHON (see below), patients with down-titration due to prostacyclin
related AEs had a sufficient efficacy for the primary endpoint. This supports the assumption that
individual tolerability is linked to individual efficacy. For the other patients in the low dose range
sufficient efficacy could not been demonstrated. Therefore, for the low dose group without dose
limiting prostacyclin related AEs, it should be considered to try to up-titrate again at a later time point.
Taken together, a bid dosing and the approach of an individual uptitration of the dose based on
tolerability is considered appropriate. Also, a dose range to be investigated in the pivotal GRIPHON trial
(200 – 1600 µg bid) is justified based on studies 304/02 (tolerability, hemodynamic endpoints and
efficacy endpoints for 200 and 400 µg single dose and 200 – 800 µg bid) and AC-065-101 (acceptable
tolerability of 200 – 1600 µg bid with a lower tolerability of 1800 µg bid).
2.5.2 Main study
The application is mainly based on one pivotal trial, the AC-065A302 "GRIPHON" study. Overall the
following studies contributed to the efficacy assessment as shown in Table 1-4:
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Pivotal trial
Study title: AC-065A302/GRIPHON: Prostacyclin (PGI2) receptor agonist in pulmonary
arterial hypertension. A multicenter, double-blind, placebo-controlled Phase 3 study
assessing the efficacy and safety of selexipag (ACT-293987) on morbidity and mortality in
patients with pulmonary arterial hypertension (PAH)
The study comprised the following periods: - Treatment period: Patients were uptitrated from 200 µg
b.i.d. to a maximally tolerated individual dose but not above 1600 µg b.i.d. (12 weeks) and patients
were kept on the maximally tolerated dose over 14 additional weeks. - Post-treatment observation
period. - Post-treatment safety follow-up, and - double blind treatment Extension period.
Patients who had an end of study (EOS) visit following a morbidity event confirmed by the CEC were
eligible to enter the extension study AC-065A303, in which all patients received open-label selexipag.
GRIPHON - study AC-065A302
Methods
The study was conducted at 181 sites in 39 countries (Asia, Australia, Europe, Latin America, and
North America), with 171 sites in 34 countries participating also in the extension study AC-
065A303/GRIPHON OL.
The following committees were involved in the conduct of the study: Steering Committee / Scientific
Advisory Board (study design and conduct of the study), Critical Event Committee (CEC, blinded to
treatment allocation and to prostacyclin- associated adverse events (AEs): adjudication of all reported
morbidity/mortality (MM) events, initially, event-adjudication was only performed to confirm the
occurrence of an MM event. Following Global Protocol Amendment 6, the process was adjusted to
adjudicate the following details: i) the presence of an MM even tii) the type of endpoint component,
iii) the MM event onset date, and iv) any PAH-association with a fatal outcome), Expert medical PAH
review committee (blinded review of baseline PAH-related characteristics), and the Ophthalmology
Safety Board (blinded to treatment allocation, reviewed ophthalmology data available from patients
enrolled in the ophthalmology sub-study), Data Monitoring Committee (DMC, unblinded efficacy, safety
and tolerability data approximately every 3 months to ensure patient safety in AC-065A302 and AC-
065A303). The DMC conducted a planned unblinded interim efficacy and safety analysis on 29 April
2013 after 206 CEC-confirmed MM events were reported and recommended the continuation of the
study.
AC-065A302/GRIPHON study design:
This was a multicenter, randomized, double-blind, parallel group, placebo-controlled, event-driven
Phase 3 study to compare the effects (efficacy, safety, tolerability,
pharmacokinetics/pharmacodynamics [PK/PD]) of selexipag (administered orally at an individualized
dose in the range of 200–1600 μg b.i.d.) versus placebo (1:1 randomization) in patients with
symptomatic PAH. In case of typical prostacyclin-associated AEs the dose was reduced by 200 µ bid
(MTD).
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The study comprised the following periods [Figure 9-1]:
- Screening period
- Treatment period: first dose on the evening of day 1 (200 µg or placebo), uptitration in weekly
increments in 200 µg bid steps until maximally tolerated individual maintenance dose (MTD) up to
week 12. At Week 12, the MTD for each patient was determined, and this dose was to be kept stable
for the next 14 weeks. After Week 26, for patients with study drug dose < 1600 μg b.i.d.,
investigators were allowed to further up-titrate the dose, if needed, by 200 μg increments up to the
maximum of 1600 μg b.i.d., only at scheduled visits. Dose reduction for tolerability was allowed.
- Post-treatment observation period (PTOP4 - refer to Figure 9-1) (added in study design following
Protocol Amendment 6): patients who discontinued study drug with or without an MM event prior to
Study closure announcement had an option to enter a post-treatment observation period to collect
additional clinical data. A post-treatment observation closure visit (PTOCV) was to be performed within
4 weeks of Study closure announcement.
- Post-treatment safety follow-up for serious adverse event (SAEs) up to 30 days after the last intake
of study drug or until administration of the first dose of selexipag in extension study AC-065A303,
whichever occurred first.
- Survival follow-up phone call4 (refer to Figure 9-1): All patients (except those who had withdrawn
consent from all study components) were contacted at the time of study closure to ascertain vital
status. Survival data up to study closure (overall study) includes patients from different phases of the
study.
- Treatment Extension period3 (refer to Figure 9-1): for patients who were receiving AC-065A302 study
drug at the time of Study closure, a double blind treatment extension period was offered that was
planned to be up to 3 months. Patients who had an EOS visit following a morbidity event confirmed by
the CEC were eligible to enter the extension study AC-065A303, if the extension study was approved
by the national Health Authority in the country.
End of study (EOS) was reached a) after an MM event or at the time of premature discontinuation of
study medication (for an individual patient), b) at the time when 331 MM events were achieved (for
the remainining patients). EOS analysis does not include the extension study AC-065A303.
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1. EOS Visit was to be performed within 4 weeks of Study closure announcement. For patients who had
a CEC-confirmed MM event or discontinued study drug before Study closure, the EOS Visit was
performed following the morbidity event or following premature discontinuation. A Post-treatment
safety follow-up phone call was performed for all patients who discontinued treatment.
2. Study closure was announced when the target number of CEC-confirmed MM events was achieved.
AC-065A303/GRIPHON OL study design:
It was an open-label, uncontrolled study following the double-blind study AC-065A302 to assess long-
term safety and tolerability of selexipag in patients with PAH. Patients from study AC-065A302 who
had a CEC-confirmed morbidity event or who completed study AC-065A302 as scheduled, and who met
the eligibility criteria were eligible to be enrolled in AC-065A303. All patients receive selexipag during
AC-065A303. The study is still ongoing.
• Study participants
Inclusion criteria
- Male and female patients aged from 18 to 75 (following Protocol Amendment 1) years inclusive with
PAH in modified NYHA/WHO FC I–IV with symptomatic PAH, both naïve to or receiving PAH specific
treatment (ERAs and/or PDE-5i, except for prostacyclin and prostacyclin analogs) were included. A
single administration of i.v./inhaled prostacyclin or analogs during a right heart catheter procedure was
allowed.
- Patients with PAH were included (Idiopathic (IPAH), Heritable (HPAH),Drug or toxin induced or
Associated (APAH) with one of the following (Connective tissue disease, Congenital heart disease with
simple systemic-to-pulmonary shunt at least 1 year after surgical repair, HIV infection.
• Documented hemodynamic diagnosis of PAH by right heart catheterization
• 6-MWD between 50 and 450 m (inclusive) at Screening
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•refrain from prolonged exposure to sun during the study
For study AC-065A303: (extension study) •Patients who had a CEC-confirmed morbidity event during
study AC-065A302 for most countries involved.
Key exclusion criteria
- Patients with pulmonary hypertension that were not covered by the inclusion criterion
- Scheduled to receive or Intake of prostacyclin (epoprostenol) or prostacyclin analogs up to 1 month
prior to the Baseline visit
- moderate or severe obstructive lung disease: FEV1/FVC < 70% and FEV1 < 65% of predicted value
after bronchodilator administration or moderate or severe restrictive lung disease: Total Lung Capacity
< 70% of predicted value
- moderate or severe hepatic impairment
- documented left ventricular dysfunction (i.e., ejection fraction < 45%, clarified by amendment 1)
- severe renal insufficiency (estimated creatinine clearance < 30 mL/min, or serum creatinine > 2.5
mg/dL)
- BMI < 18.5 kg/m2 (modified by amendment 1)
- Lactating or pregnant
- Following Protocol Amendment 1, exclusion criterion on hypotensive patients was removed.
• Treatments
Film-coated tablets containing 200 μg selexipag or matching placebo (AC-065A302).
The first dose was taken on the evening of day 1 (200 µg or placebo), uptitration in weekly increments
in 200 µg bid steps until maximally tolerated individual maintenance dose (MTD) up to week 12 and up
to 1600 m (8 tablets).
Objectives
Primary objective
• To demonstrate the effect of selexipag on time to first MM event in patients with PAH.
Secondary objectives
• To evaluate the effects of selexipag on exercise capacity and other secondary and exploratory
efficacy endpoints in patients with PAH.
• To evaluate the safety and tolerability of selexipag in patients with PAH.
• Outcomes/endpoints
Primary efficacy endpoint
The primary efficacy endpoint was the Time to first CEC-confirmed MM event up to 7 days after the last
study drug intake in the AC-065A302 treatment period (i.e., end of treatment [EOT] + 7 days). MM
events included • Death (all-causes) • Hospitalization for worsening of PAH based on predefined
criteria • Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy •
Initiation of parenteral prostanoid therapy or chronic oxygen therapy due to worsening of PAH •
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Disease progression confirmed by: – Decrease in 6MWD from Baseline (in patients with NYHA/WHO FC
II or III at baseline, ≥ 15%, confirmed by 2 tests on different days within 2 weeks) and – Worsening of
NYHA/WHO FC • Disease progression (in patients in NYHA/WHO FC III or IV at baseline) confirmed by:
– Decrease in 6MWD from Baseline (≥ 15%, confirmed by 2 tests on different days within 2 weeks)
and – Need for additional PAH-specific therapy.
Key secondary endpoints were :
. change from baseline to Week 26 in
- 6MWD measured at trough
- Absence of worsening in NYHA/WHO FC
. Time from randomization to
- first of CEC-confirmed death due to PAH or CEC confirmed hospitalization due to PAH up to 7
days after end of treatment
- death of all causes up to Study closure
• Sample size
It was initially estimated that a total of 202 MM events confirmed by the CEC were needed to obtain an
overall power of 90% for rejection of the null hypothesis (at two sided alpha 0.01), assuming a hazard
ratio of 0.5729 for selexipag versus placebo over the estimated maximum study duration of 3.5 years.
The originally assumed hazard ratio of 0.5729 was largely based on previous monotherapy studies in
patients in WHO FC III/IV and was later amended to 0.65, taking into account the predominant
enrolment of patients in GRIPHON in FC II and III, and on background PAH therapy. To detect this
amended treatment effect without changing the protocol requirements for the Type I and Type II error
rates, and within the study timelines, an increase of the number of primary events to 332 and of the
sample size to 1150 patients was required. At the same time a group-sequential design with one
interim analysis to be conducted by the Independent Data Monitoring Committee after the originally
projected 202 confirmed MM events (an information fraction of f = 202/331 = 0.61) was introduced.
Based on Protocol Amendment 6 there were further changes to calculation of the sample size and
assumptions: A total of 331 confirmed MM events were needed in order to obtain an overall power of
90% for rejection of the null hypothesis. With the recruitment of up to 1150 patients randomized 1:1
to active treatment and placebo over a period of 3.1 years, the number of events was expected within
a maximum of 4.3 years.
Randomisation
In study AC-065A302 eligible patients were randomized in a 1:1 ratio to selexipag or placebo using a
centralized randomization system via IVRS.
Blinding (masking) Study AC-065A302 was performed in a double-blind fashion.
• Statistical methods
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The null hypothesis was that there was no difference between selexipag and placebo for time to first
confirmed MM event. The primary statistical analysis was performed on the Full Analysis Set (FAS) by a
one-sided unstratified log-rank test in a group-sequential setting. A number of supportive analyses to
the primary endpoint were performed using different tests and models.
A group-sequential design with one interim analysis to be conducted by the Independent Data
Monitoring Committee after the originally projected 202 confirmed MM events (an information fraction
of 202/331 = 0.61) was introduced by amendment. The group-sequential design used a one-sided
overall type I error level of 0.005, maximum information was specified as 331 first MM events, and the
one-sided type I error level at the interim analysis was fixed to 0.00005. The change in the target
hazard ratio was initially discussed with the FDA (Amendment 4 of the protocol). In order to eliminate
any concern that the protocol changes based on global Amendment 4, submitted on August 16th 2011
to the FDA, could be considered informed, MM events with a confirmed onset date up to August 16th
2011 were censored and were not considered in the primary analysis.
Hierarchical testing was stipulated in the protocol following the list of secondary endpoint as described
below. This procedure controls the family-wise type I error rate on a one-sided alpha level of 0.005
(two-sided alpha of 0.01).
Confirmed MM events, including those with onset date up to August 16th 2011 were included as events
in the secondary analyses and additional analyses.
The analyses of the primary endpoint including or excluding components up to study closure used a
one-sided unstratified log-rank test (at the corresponding one-sided overall type I error level defined
by the group-sequential design).
The first secondary endpoints analysed in a hierarchical procedure were (1) the absolute change from
baseline in 6MWD at trough at Week 26 analyzed by a non-parametric analysis of covariance
(ANCOVA), (2) absence of worsening from baseline to Week 26 in WHO FC was analysed by 2-sided
Cochran-Mantel-Haenszel test stratified by WHO FC at baseline, (3) time from randomization to first of
confirmed death due to PAH or confirmed hospitalization due to PAH worsening up to 7 days after last
study drug intake was analyzed by a one-sided unstratified log-rank test and (4) time to death up to
study closure using a one-sided unstratified log-rank test.
The analyses of changes in 6MWD and WHO FC over time were performed descriptively.
GCP
Generally, there were no indications that the studies were not conducted appropriately. One inspection
report from DCGI India regarding the Site #6501 Dr. Kohli, Delhi was requested. The applicant stated
that no report was to be expected from DCGI. The issue is not considered relevant for the overall
conclusions since only 1 patient was randomised in this center. After additional explanations, an initial
concern related to partial unblinding for 280 patients in 27 centres to the clinical supply manager and
unblinding due to typical AEs was not considered to be relevant for the reliability of the data or the
integrity of the study.
Results
AC-065A302
Baseline characteristics and study discontinuations
A total of 1156 patients were randomized in a 1:1 ratio to selexipag (N = 574) or placebo (N = 582). A
total of 27.0% and 41.6% of patients in the selexipag and placebo groups, respectively, discontinued
with a CEC-confirmed Morbidity/Mortality (MM) event up to EOT + 7 days. The proportion of patients
who discontinued prior to Study closure with no CEC-confirmed MM event up to EOT + 7 days was
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22.6% in the selexipag group and 15.1% in the placebo group. 113 and 137 patients in the selexipag
and placebo groups, respectively, consented to participate in the post-treatment observation period
(PTOP). The disposition of patients is summarized in Table 15-1 and in Figure 10-1.
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A total of 218 patients (63 previously randomized to selexipag, 155 previously randomized to placebo)
were enrolled into the extension study AC-065A303. All 218 patients received selexipag in study AC-
065A303.
The study population was predominantly female (79.8%). Median age at screening was 49.0 years,
and approximately 18% of the patients were elderly (≥ 65 years). Most of the patients were
Caucasian/White (65.0%) or Asian (21.2%). Median time from PAH diagnosis was 1.0 year. The most
common PAH etiology was idiopathic (56.1%), followed by PAH associated with connective tissue
disease (28.9%) or congenital heart disease (9.5%). Only few patients with heritable, drug or toxin
induced, or HIV infection mediated PAH were included (0.9 – 2.3% with 10 – 27 patients of the total
number of subjects randomized). At baseline, patients were predominantly in NYHA/WHO FC II
(45.8%) and FC III (52.5%). Only 9 patients in FC I and only 11 in FC IV were randomized. The
median 6MWD of 372.0 m and the median Borg dyspnea index of 3.0 at baseline correspond to this FC
distribution. Similar proportions of patients in each treatment group (80.5% selexipag, 78.7% placebo)
were receiving background PAH-specific therapy at baseline, mainly PDE-5 inhibitor monotherapy
(32.9% selexipag, 31.8% placebo) or combination therapy with ERA and PDE-5 inhibitor (31.2%
selexipag, 33.8% placebo). Patients entering study AC-065A303 tended to have more severe disease.
Maintenance doses of selexipag
The individual maintenance dose in the selexipag group and in the placebo group are shown in Table
11-1
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28.4% of the patients reached the maximal dose level with selexipag, 67.5% with placebo. The
placebo data indicate that in some of the patients dose titration by tolerability may not lead to the
optimal dose because non-specific events are a reason not to increase the dose further. . In clinical
practice, trying to increase the dose again at a later time point may be appropriate for such
patients.
Efficacy results
The median double-blind on-treatment period was 70.7 weeks in the selexipag and 63.7 weeks in
the placebo group, respectively. The proportion of patients who experienced a CEC-confirmed MM
event up to 7 days after last study drug intake was 24.4% (140 patients) in the selexipag group
compared to 36.4% (212 patients) in the placebo group (Figure 11-1). The primary efficacy
endpoint showed a clear and significant effect favoring selexipag. There was a numerical difference
of 72 events between the groups favoring selexipag.
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The observed treatment effect was consistent across subgroups (Figure 11-7). Only for the Asian race
and the subgroups of Asia and North America (geographical region), the hazard ratio for selexipag
versus placebo was close to 1.
For the overall primary analysis shown above according to amendment 5 (the assumed hazard ratio
was increased from 0.5729 to 0.650 and consecutively the planned sample size was increased from
670 to 1150 patients) events up to 16 Aug 2011 were not counted in order to eliminate any concern
that the protocol change could be considered informed. Overall, the results were consistent for the
analyses including these events. When events up to August 16 2011 were included the proportion of
patients who experienced a CEC-confirmed MM event up to 7 days after last study drug intake was
27.0% (155 patients) in the selexipag group compared to 41.6% (242 patients) in the placebo group. .
Table 11-4 summarizes the first CEC-confirmed MM event up to EOT + 7 days excluding events up to
August 16, 2011.
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Table 11-4 summarizes the first CEC-confirmed MM event up to EOT + 7 days including events up to
August 16, 2011.
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A competing risk analysis showed that all 4 components of the primary efficacy endpoint components
competed with each other during the treatment period since the occurrence of one prevented the
observation of the others up to 7 days after last study drug intake. Patients in the selexipag group
showed a lower risk of disease progression (p < 0.0001) and hospitalization for PAH worsening (p =
0.0402) than patients in the placebo group. No significant difference was observed between selexipag
and placebo for the risk of PAH worsening (p = 0.5342).
(Fig. 11-8).
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The number of patients who experienced, as a first event, death due to PAH or hospitalisation for PAH
up to end of treatment was 102 (17.8%) in the selexipag group and 137 (23.5%) in the placebo
group. Death due to PAH as a component of the endpoint was observed in 16 (2.8%) patients on
selexipag and 14 (2.4%) on placebo. Hospitalisation for PAH was observed in 86 (15.0%) patients on
selexipag and 123 (21.1%) patients on placebo. Selexipag reduced the risk of hospitalisation for PAH
as a first outcome event compared to placebo (HR 0.67, 99% CI: 0.46, 0.98; one sided log rank p =
0.04).
Effect of selexipag on mortality
Death as a first event was in favour of placebo (4.9 vs. 3.1%, 28 vs. 18 events) (censored analysis:
4.4 vs. 2.7%, 25 vs. 16 events) almost reaching statistical significance (p = 0.0827). The unfavourable
trend emerged after about 18 months of treatment. Median treatment duration was different in the
selexipag (70.7 weeks) vs. the placebo (63.7 weeks) group. Adjustment for this difference reduced but
did not remove the numerical difference in mortality at EOT: taking into account the treatment
duration, mortality rate (deaths per 100 patient years) was 5.45 in the selexipag and 4.64 in the
placebo group, yielding a hazard ratio (HR) of 1.17.
The GRIPHON trial was event-driven and designed to stop treatment of an individual patient after their
first primary outcome event, which was usually a disease progression (morbidity) event. Experiencing
a morbidity event was associated with a higher risk of dying.
Up to EOT, more morbidity events occurred in patients on placebo than in patients on selexipag (205
vs. 109 respectively). Consistently, in the post-treatment observation period (PTOP), more patients
entering from the placebo group (17/137, 12.4%) died than patients entering from the selexipag group
(11/113, 9.7%). Not all patients entered the subsequent extension study (in which all patients
received open-label selexipag). Death rate was generally higher in patients not participating vs. those
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participating in the extension study: for patients having already received selexipag in the parent study,
the difference in death rate was 0.41 vs. 0.33 per patient year, respectively; (patients after a CEC
confirmed M&M event). For patients coming from the placebo group, the difference in death rate was
0.37 vs. 0.22 per patient year, respectively.
A number of additional analyses were performed to address aspects of the results for the mortality
component of the primary endpoint.
According to the analyses, death rates up to EOT are biased by informative censoring. Informative
censoring occurs when events are not counted in the analysis due to reasons related to the study
design.
Since more morbidity events occurred in the placebo group, more patients at high risk were excluded
from further follow-up in the placebo group than in the selexipag group with a consequence that
follow-up is shorter in the placebo group and follow-up from more patients that are at higher risk is
excluded from the placebo group, resulting in bias. Observation of the patient is ‘censored’ when
follow-up is discontinued according to the protocol definition and because the risk for those patients is
probably increased, the censoring is termed ‘informative’ for outcome (patients at increased risk are
more likely to be censored). In other words, due to the study design, the risk profile of the patients
changed during the course of the study, favouring placebo group at the end of the trial despite of
randomization. This is consistent with the observation that the imbalance did not emerge before month
18.
In order to further evaluate the overall effect of informative censoring on the treatment comparison for
survival, an analysis as proposed by Denne et al. 2013 was conducted by the applicant. The method
compares the event rates in the study arms prior to censoring with the follow-up period after EOT +7
days up to study closure. If the censoring would be non-informative (i.e. if morbidity and mortality
events would be independent from one another), the ratio of the event rates (censoring event rate
ratio, CERR) would be expected to be 1.0. The observed CERR was 4.8 in the placebo group and 4.2 in
the selexipag group indicating that patients censored are at a considerably greater risk of death
compared to patients not censored in both treatment arms.
Additionally, a “landmark analysis” as proposed by Anderson et al 1983 was performed. This analysis
compares survival between patients with and without a morbidity event prior to the landmark time
points 3, 6, 12 and 18 months. In both treatment arms, the hazard ratio for death was significantly
increased for patients with a morbidity event compared to patients without a morbidity event at all
time points. In the selexipag group, the hazard ratio decreased slightly over time. This analysis
supports the view that a morbidity event is associated with an increased risk of death.
Up to study closure a total of 100 and 105 patients in the selexipag and placebo groups died,
respectively (Fig. 10-1, and Fig. 11-13). In this analysis patients were included that, after the first
M&M event, either remained on selexipag, discontinued treatment or switched from placebo to
selexipag in the extension study. This implies that patients on placebo could cross over to treatment
with selexipag and this cross-over could have an impact the mortality estimates.
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The applicant presented two analyses to explore the impact of cross-over from the placebo arm and
treatment discontinuations in the selexipag arm on the mortality up to study closure. These are a Rank
Preserving Structural Accelerated Failure Time Model (RPSFT Model) and an approach using a Marginal
Structural Cox Proportional Hazards Model with time-dependent weights according to the Inverse
Probability of Censoring Weighting (IPCW) scheme. For both approaches, the RPSFT and Structural
Proportional Hazards Model analyses, patients were considered on “active treatment” if they were
treated with selexipag or with an agent targeting the same pathway as selexipag. The number of
patients in both treatment arms receiving prostacyclin and analogues with the same target as
selexipag after study drug discontinuation was similar (40 in the selexipag arm, 44 in the placebo
arm). Considering selexipag and agents targeting the same pathway as selexipag as “active
treatment”, patients in the selexipag arm were about 85% of their observation time on active
treatment and patients in the placebo arm were about 16% on active treatment.
The results RPSFT Model provide a valuable estimate of relative survival on active treatment compared
to no treatment of 1.19 with a quite wide 95% confidence interval of (0.56, 2.05).
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Using the Structural Proportional Hazards Model with IPCW weighting the estimate for the hazard ratio
for death as if all patients had received active treatment compared to the situation if all patients had
never received active treatment was 0.92 with a 95% confidence interval of (0.58, 1.47) for the 1
month time intervals, showing a slight advantage for treatment with selexipag. Both estimations with
models with longer time intervals show non-significant lower hazard ratios (0.79 and 0.75).
A subgroup analysis for mortality indicated that the imbalance favouring placebo was restricted to
patients in WHO FC I/ÌI (HR 1.70, (99% CI 0.59, 4.91), death up to EOT + 7 days, p=0.28). The
analysis up to study closure showed a significant treatment by subgroup interaction for NYHA/WHO FC
at baseline (p=0.0346) with a HR for FC I/II of 1.69 (0.80; 3.56) favouring placebo.
The Applicant submitted two independent mathematical simulations in order to model the observed
pattern of mortality. The observed data could be fitted well with two assumptions: First, selexipag has
a neutral effect on mortality, i.e. mortality is neither increased nor reduced by selexipag intake.
Second, selexipag reduces non-fatal but not fatal endpoint events during treatment. This assumption
was needed to explain the higher proportion of mortality among the endpoint events with selexipag as
compared to placebo.
The simulations showed that the probability to observe a large imbalance for death as first event of 10
(or more) is in the range of 30% to 51% and for death up to EOT+7d of 9 (or more) is in the range of
26% to 47%. The probability to observe any imbalance with more deaths as first event for selexipag
would be typically higher than 70%.
Additional discussion is provided in section 2.6.1 Discussion on clinical safety.
A post-morbidity event survival analysis by treatment path was conducted [Figure 4]. The Kaplan-
Meier survival estimate was better in patients treated with selexipag in the OL extension study (AC-
065A303/GRIPHON OL), than in patients treated with standard of care (SoC) outside GRIPHON OL,
irrespective of their original treatment allocation. Of note, patients were not randomly allocated in this
analysis and it cannot be clarified whether deteriorating patients may have preferentially received
selexipag or standard of care. Since pre-treatment status (selexipag or placebo) did not appear to
have a major impact on outcome during the open label phase, the data do not suggest selexipag to
have a beneficial disease modifying effect beyond treatment time.
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The Applicant also provided a post-hoc analysis using the primary endpoint as proposed by the CHMP
guideline on PAH.
Notably, the composite endpoint recommended in the respective CHMP guideline includes right-sided
heart failure, which was not part of the primary composite endpoint in GRIPHON. With this analysis,
death as an overall first event was essentially balanced between the selexipag and placebo groups
(2.4% vs. 2.1%, see table below).
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The incidence of the components of the CHMP-defined endpoint are displayed in the table below (first
event in each category analysis, a patient may be counted in more than one category).
When using the CHMP proposed primary composite endpoint, the results in all predefined subgroups
were consistently in favour of selexipag (HR between 0.26 and 0.89) with the exception of patients on
previous ERA monotherapy (HR 1.29 (0.74; 2.22 99% CI) and the geographical region North America
(HR 1.18 (0.79; 1.98)).
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6-MWD
Median absolute change from Baseline to Week 26 in 6MWD measured at trough was 4.0 m in the
selexipag group and −9.0 m in the placebo group. The difference was statistically significant (1-sided
Wilcoxon-Mann-Whitney p = 0.0027). The treatment effect (location shift using Hodges-Lehmann
method) versus placebo in the selexipag group was 12.0 m (99% CI: 1, 24). Mean change was -52.00
m and -66.26 m, respectively. There was a significantly lower incidence of patients in the selexipag
group (198 patients, 34.5%) compared to the placebo group (284 patients, 48.8%) who experienced a
drop (deterioration) in 6MWD ≥ 15% during the GRIPHON treatment period (see Table 52 below). The
treatment effect on the 6MWD was larger in treatment naïve patients (difference of +34 m vs. placebo
at the pre-defined timepoint of 6 months (99% CI: 10.0; 63.0, 1-sided Wilcoxon-Mann-Whitney p =
0.0002)) compared to patients pretreated with ERA, PDEi or ERA+ PDEi (location shift -1 (-38.0; 28.0
m), +12.0 (-8.0; 33.0m), and +6.0 (-14.0; 24.0 m), respectively). It was larger in patients with FC
III/(IV) (+17.0 (-1.0; 36m) compared to patients with FC (I)/II (+5.0 (-8.0; 19.0 m).
Change from baseline in NYHA/WHO FC
At all time points, the proportion of patients with non-missing values who had improved FC compared
to Baseline was greater in the selexipag group than in the placebo group. The proportion of patients
with non-missing values who had worsened FC compared to Baseline was lower in the selexipag group
than in the placebo group except for week 4, month 6 and month 24.
Quality of life (Cambridge Pulmonary Hypertension Outcome Review)
For the overall symptom score, the treatment effect (median absolute change from Baseline to Week
26) of selexipag versus placebo was 0.0 (99% CI: −1.0, 1.0, p = 0.2185). For the sub-scale
‘Breathlessness’ the treatment effect of selexipag versus placebo was 0.0 (99% CI: −0.4, 0.0, p =
0.1700).
Plasma NT pro-BNP
The absolute change from Baseline to end of treatment (corresponding to individual patients end of
study visit) in median plasma NT pro-BNP was 5.5 ng/L (range: −4790 to 10873) in the selexipag
group compared to 75.0 ng/L (range: −7309 to 41586) in the placebo group, mean absolute changes
from baseline were 271.7 (SD 1337.6) vs. 659.6 (SD 2976.3) ng/mL, respectively.
Efficacy by individual maintenance dose
For the primary efficacy endpoint there was no clear correlation between dose and treatment effect.
The hazard ratios versus placebo for the occurrence of an MM event in the selexipag IMD categories
were:
• selexipag IMD category 200–500 μg b.i.d.: 0.60 (95% CI: 0.41, 0.88, 1-sided unstratified log-rank p
= 0.0038),
• selexipag IMD category 600–1100 μg b.i.d.: 0.53 (95% CI: 0.38, 0.72, 1-sided unstratified log-rank
p ˂ 0.0001), and
• selexipag IMD category 1200–1600 μg b.i.d.: 0.64 (95% CI: 0.49, 0.82, 1-sided unstratified log-rank
p = 0.0002).
For the 6-MWT
median/mean absolute changes from Baseline to Week 26 in 6MWD measured at trough in the
selexipag IMD categories were
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• selexipag IMD category 200–500 μg b.i.d.: −20.0 m/ -115.68 m
• selexipag IMD category 600–1100 μg b.i.d.: 8.5 m/-43.66 m
• selexipag IMD category 1200–1600 μg b.i.d.: 15.0 m/-7.75 m
• placebo: −9.0 m/-66.26
Table 1: Summary of efficacy for trial AC-065A302/GRIPHON
The following table summarise the efficacy results from the main studies supporting the present
application. These summaries should be read in conjunction with the discussion on clinical efficacy as
well as the benefit risk assessment (see later sections).
Study identifier
AC-065A302/GRIPHON including data from AC-065A302 post
treatment observation period
Design
Multicenter, randomized, double-blind, parallel group, placebo-controlled,
event-
driven Phase 3 study to compare the effects (efficacy, safety, tolerability,
pharmacokinetics/pharmacodynamics [PK/PD]) of selexipag (administered
orally at an individualized dose in the range of 200–1600 μg b.i.d.) versus
placebo (1:1 randomization) in patients with symptomatic PAH
median duration of double-
blind study treatment:
selexipag: 70.7 weeks (range: 0.3–216.7
weeks)
placebo: 63.7 weeks (range: 0.7–192.0 weeks)
Duration of Extension phase:
ongoing
Hypothesis
Superiority selexipag vs. placebo
Treatments groups
Selexipag
Selexipag individual dose titration 200 µg bid –
1600 µg bid in 200 µg bid steps until maximally
tolerated individual maintenance dose, number
randomized 574
Placebo
Placebo, number randomized 582
Endpoints and
definitions
time from
randomizat
ion to first
CEC-
confirmed
MM
event up to
7 days
after last
study drug
intake
composite
- Death (all causes) or
- Hospitalization for worsening of PAH based on
predefined criteria
- Worsening of PAH resulting in need for lung
transplantation or balloon atrial Septostomy
- Initiation of parenteral prostanoid therapy or
chronic oxygen therapy due to
worsening of PAH
- Disease progression: Decrease in 6MWD from
Baseline and
a) Worsening of NYHA/WHO FC (patients in FC
II-III)
b) Need for additional PAH-specific therapy
(patients in FC III-(patients in FC III-IV)
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Secondary
endpoint
6-MWT
No worsening
PAH death or
PAH hosp
All-cause
death
Breathlessness
CAMPHOR
- Absolute change from Baseline to Week 26 in
6MWD measured at trough
- Absence of worsening from Baseline to Week
26 in NYHA/WHO FC
- Time from randomization to first of CEC-
confirmed death due to PAH or CEC confirmed
hospitalization due to PAH worsening up to 7
days after last study drug intake in the AC-
065A302 treatment period.
- Time from randomization to death of all
causes up to Study closure.
- Absolute change from Baseline to Week 26 in
the sub-scale ‘Breathlessnessʼ of
CAMPHOR (Cambridge Pulmonary Hypertension
Outcome Review) ‘Symptoms
- Absolute change from Baseline to Week 26 in
CAMPHOR ‘Symptomsʼ score
exploratory
NT pro-BNP
And others
Database lock
First patient, first visit: 30 Dec 2009
Last patient, last visit (in AC-065A302 treatment period): 27 Apr 2014
Results and Analysis
Analysis description
Primary Analysis
Analysis population
and time point
description
The primary statistical analysis for the primary composite endpoint was
performed on the Full Analysis Set for the time to the first primary endpoint
event excluding data up to August 16, 2011 (a) (amendment 5). Results
including all data are also listed (b).
Descriptive statistics
and estimate
variability
Treatment group
Selexipag
Placebo
Number of
subject
574
582
Effect estimate per
comparison
Primary endpoint
Primary endpoint
components
Death
Hospitalization for
worsening of PAH
Worsening of PAH
(lung
transplantation or
atrial
septostomy)
Prostanoid or
oxygen therapy
due to worsening
of PAH
Disease
progression
a) 140 patients (24.4%)
p < 0.0001
b) 155 patients (27.0%)
a) 25 (4.4%)
b) 28 (4.9%)
a) 71 (12.4%)
b) 78 (13.6%)
a) 1 (0.2%)
b) 1 (0.2%)
a) 11 (1.9%)
b) 10 (1.7%)
a) 32 (5.6%)
b) 38 (6.6%)
a) 212 patients (36.4%)
b) 242 patients (41.6%)
a) 16 (2.7%)
b) 18 (3.1%)
a) 96 (6.5%)
b) 109 (18.7%)
a) 2 (0.3%)
b) 2 (0.3%)
a) 14 (2.4%)
b) 13 (2.2%)
a) 84 (14.4%)
b) 100 (17.2%)
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6-MWT
Baseline values
mean (SD)
median
median change
mean change
(SD)
no worsening
358.5 (76.3) m
376.0 m
348.0 (83.2) m
369.0 m
4.0 m
-9.0 m
-53 (150.24) m
- 66 (148.23) m
77.8%
74.9%
PAH death or PAH
hosp.
All-cause death
Breathlessness
CAMPHOR
102 (17.8%)
137 (23.5%)
100 (17.4%)
105 (18.0%)
0.0
0.0
−1.0
0.0
Notes
According to analyses the higher rate in mortality events as a primary
endpoint component may be due to informative censoring.
Clinical studies in special populations
No studies in special populations were conducted. The pivotal GRIPHON study included a wide variety
of patients with PAH.
Analysis performed across trials (pooled analyses AND meta-analysis)
No pooled analyses or meta-analyses were provided by the applicant for efficacy evaluation.
Supportive studies
Study AC-065A201
An interim report of a multicentre, uncontrolled, phase 2 open label clinical study in Japanese patients
with PAH was provided. The interim report includes the results up to Week 16 of treatment with
selexipag. Albeit uncontrolled, treatment of 37 patients with PAH over 16 weeks with selexipag was
associated with small – moderate beneficial effects on pulmonary haemodynamics, as decreases in
pulmonary vascular resistance, pulmonary artery pressure, and small increases in cardiac output and
cardiac index. The mean performance in the 6-MWT test improved, but without a placebo control the
data cannot be considered as a measure of a true treatment effect. No beneficial effect was seen on
the Borg dyspnea index.
Study AC-065B201
Study AC-065B201 was an exploratory controlled, double blind, multicentre study in 34 Japanese
patients with chronic thromboembolic pulmonary hypertension (CTEPH).
Selexipag was associated with small – moderate beneficial effects on pulmonary haemodynamics, as
decreases in pulmonary vascular resistance, pulmonary artery pressure, and small increases in cardiac
index.
There was no beneficial effect on the 6 MWT: The mean treatment effect (95% CLs of difference in
mean) selexipag was lower than with placebo: -9 m (-57 to 39 m). No beneficial effect was seen on
the Borg dyspnea index.
Study AC-065B202 was an open label extension study of study AC-065B201.
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28 patients were treated open label with selexipag. There were small changes in the 6-MWT, the BORG
dyspnea scale and WHO function class. The data do not indicate a detrimental effect on efficacy
parameters with selexipag in the long term treatment of patients with CTEPH.
2.5.3 Discussion on clinical efficacy
Design and conduct of clinical studies
The clinical program was mainly based on 1 controlled pivotal phase III study, the GRIPHION trial, in
patients with PAH of different origin.
Prior to initiation of the GRIPHON trial (AC-065A302, 1156 patients) Study NS-304/02 was conducted,
containing 2 parts, a multicenter, open-label, single-dose, acute hemodynamic study (43 patients)
followed by a multicenter, randomized, double-blind, parallel-group, placebo-controlled study over 21
weeks in 43 patients with PAH. Dose selection for the phase III study based on these studies was
considered appropriate.
The design of the pivotal study (GRIPHON trial) was largely in agreement with the requirements of the
relevant EMA guideline EMEA/CHMP/EWP/356954/2008. The applicant used a combined endpoint
(death, hospitalization for worsening of PAH based on predefined criteria, worsening of PAH resulting in
need for lung transplantation or balloon atrial septostomy, initiation of parenteral prostanoid therapy
or chronic oxygen therapy due to worsening of PAH, and disease progression). Signs or symptoms of
right heart failure have not been included in the primary endpoint as opposed to the proposal of the
guideline. The Applicant provided a post-hoc analysis using the composite endpoint suggested by the
Guideline in PAH. The results were largely consistent with the results of the predefined primary efficacy
endpoint. After inclusion of right heart failure as a first event, the difference in primary mortality
events between selexipag and placebo decreased.
The choice of the primary endpoint in combination with the decision to discontinue selexipag in
patients after the first primary endpoint event with the possibility to switch placebo patients to
selexipag after the first event turned out to be a relevant drawback of the design. A large difference
between the groups for “disease progression (as a component of the primary endpoint)” was a major
obstacle to reliably assess all-cause mortality.
The primary efficacy endpoint was accompanied by relevant secondary endpoints including the single
components of the primary endpoint and 6- MWT, quality of life, Borg dyspnea scale, and biomarkers.
Generally, there were no indications that the studies were not conducted appropriately.
At study closure (i.e., when the overall target number of 331 CEC confirmed MM events was achieved),
vital status of 24 patients (4.2%) and 27 patients (4.6%) in the selexipag and placebo groups,
respectively, was reported as not known. However, the impact on the overall study results is limited,
as has been demonstrated by additional analyses provided.
Study population
The number of patients included was overall appropriate (selexipag: 574, placebo: 582). In fact up to
now, GRIPHON is the largest trial conducted in patients with PAH. The median duration of double-blind
study treatment was 70.7 weeks in the selexipag group compared to 63.7 weeks in the placebo group,
with 63.8% and 62.6% of patients in the respective groups receiving study treatment for at least 1
year. The data are sufficient to support long term maintenance of efficacy.
The patient populations were well characterized based on accepted clinical and haemodynamic criteria,
mainly patients in WHO II and III. Overall the patient population included in the clinical trials is
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representative of the population of the intended indication. More than 50% of patients had idiopathic
PAH, almost 30% connective tissue disease, around 10% congenital heart disease. Other groups of
patients (heritable, drug or toxin induced, HIV infection) had a low representation (0.9 – 3.0%, 5 – 17
patients). Similarly, only few patients in NHYA I and IV (3 – 8 per group) were included. Therefore,
only patient with idiopathic PAH and connective tissue disease in stages II – III were sufficiently
represented in the study in order to be reflected in the wording of an indication. Efficacy data were
provided separately for IPAH, HPAH, and HIV associated and drug induced PAH. The representation of
heritable and idiopathic PAH in GRIPHON was similar to SERAPHIN (Opsumit, macitentan).
The wording of the indication for Opsumit (macitentan) includes both heritable and idiopathic PAH as
follows: “Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH
associated with …”. A consistent wording including IPAH and HPAH is acceptable for selexipag. Patients
in FC I and in FC IV are not included in the final wording of the indication due to the limited data
available in this patient population.
The treatment groups were generally balanced regarding demographics and disease characteristics.
However, a slightly higher proportion of patients in NYHA/WHO FC III/IV and a somewhat lower mean
baseline 6MWD was noted in the placebo group, compared to selexipag. According to a sensitivity
analysis this was not of relevance for the overall study result.
Most patients (80.5% selexipag, 78.7% placebo) were receiving PAH-specific medication at baseline
consisting of ERA monotherapy (16.4/13.1%), PDE5 inhibitor monotherapy (32.9/31.8%) or both
(31.2/33.8%). The use of placebo as a comparator in the GRIPHON study is considered to be ethically
acceptable in patients receiving background therapy with approved specific PAH medication. The
Applicant ensured that patients who were not receiving PAH-specific medications at baseline were not
unduly exposed to any increased risk due to their participation in GRIPHON.
Statistical methods
The statistical methods used were well described in all studies and generally considered appropriate.
The issue of missing values is handled appropriately by providing sensitivity analyses. Post hoc,
additional analyses were performed in order to assess if the issue of increased mortality with selexipag
in the first event analysis and whether this finding could be explained by informative censoring.
Overall, the methods appear to have been appropriately applied. An additional analysis relating to
grouping of selexipag with other drugs with the same presumed pathway of action confirmed the initial
analysis.
The blinded expert medical review revealed that 6.7% of the patients had baseline characteristics
atypical for PAH, 76.4% typical and 17.0% consistent baseline characteristics. The applicant to
provided data supporting consistency of the results for 3 groups.
Maintenance dose
With respect to dose some patients may have not been uptitrated appropriately due to non-specific
AES. In clinical practice, trying to increase the dose again at a later time point in patients initially not
tolerating the maximal dose may be appropriate.
Efficacy data and additional analyses
The results on the primary efficacy endpoint showed a clear and significant effect favoring selexipag.
The proportion of patients who experienced a CEC-confirmed MM event up to 7 days after last study
drug intake (EOT+ 7d) was 24.4% in the selexipag group compared to 36.4% in the placebo group.
There was a numerical difference of 72 events between the groups favoring selexipag. The overall
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effect on the primary endpoint was consistent for hospitalization for PAH, parenteral prostanoid or
oxygen therapy. It was mainly driven by “disease progression” (decrease in 6 MWD accompanied
either by a decrease in FC or by the need for additional PAH therapy): Selexipag 71 (12.4%) vs.
placebo 96 (16.5%). On the other hand there was an imbalance for all-cause mortality favoring
placebo (Selexipag 25 (4.4%), Placebo 16 (2.7%)). A similar numerical imbalance in deaths was
observed for other secondary survival endpoints in the FAS and safety analysis sets EOT +7 days and
EOT+30 days.
The Applicant conducted a number of additional analyses to address aspects of the results for the
mortality component of the primary endpoint. In subgroup analyses the difference was attributable to
an imbalance in patients with NYHA II and not with NYHA III. Similarly, the difference was observable
in patients with better cardiac function but not in patients with poor cardiac function (reference is
made to the safety section of this report). The analysis of time to death until study closure showed no
difference in mortality between selexipag and placebo for the whole group of patients However, in the
subgroup of patients with FC I/II, mortality was still increased at study closure (HR 1.69). Additional
analyses indicated that the analysis at end of treatment +7 days underestimates the risk of death in
both arms and that the degree of underestimation is higher in the placebo group. The analyses are
hampered by the fact that some patients from the placebo group switched to selexipag in the
extension study, whereas other patients from the selexipag group did not enter the open label
extension period on selexipag. Two models accounting for cross-over (i.e. a Rank Preserving Structural
Accelerated Failure Time Model and a Marginal Structural Cox Proportional Hazards Model (with IPCW))
indicated that treatment with selexipag might in the best case even be associated with an
improvement in mortality by up to about 25%. Two additional simulations were performed which
indicated that an imbalance for death as first event up to EOT or EOT+7d is not an unexpected result
under the assumption that selexipag decreases non-fatal but not fatal events. The results showed that
the probability to observe a large imbalance for death as first event of 10 (or more) is in the range of
30% to 51% and for death up to EOT+7d of 9 (or more) is in the range of 26% to 47%. The
probability to observe any imbalance with more deaths as first event for selexipag would be typically
higher than 70%.
Taken together, the mortality data are complex to assess. At the primary analysis timepoint EOT+7d,
selexipag appeared to have a negative effect on mortality as the primary endpoint component,
whereas the analysis up to study closure in the full analysis set (FAS) suggested a neutral effect and
mathematical models which take into account cross-over even indicated an up to 25% reduction in
mortality. These models should however be interpreted with caution because in any such model
assumptions have to be made.
Exclusion of a detrimental effect on survival is a key aspect for a new drug in this therapeutic field
(EMEA/CHMP/EWP/356954/2008). The additional analyses provided supported the assumption that the
increase in mortality after month 18 can be explained by informative censoring. i.e., since selexipag
was effective in reducing morbidity events, more patients in the placebo arm were taken off study
medication after a first morbidity event. Since these are patients at increased risk to die, an imbalance
developed during the study favouring placebo with respect to the risk of dying.
Simulations indicated that there was a high probability for an imbalance with more deaths as first
event for selexipag in case the overall effect on mortality was neutral.
In addition, when signs and symptoms of right heart failure are taken into account, as proposed by
the respective CHMP guideline, the difference for death as a first event is small (14 vs. 12 events
selexipag vs. placebo). No difference in mortality was observed when patients were analysed according
to Benza disease severity category, a key predictor of survival in patients with PAH (Benza RL et al.
Circulation 2010).
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Mortality as a first overall event up to EOT+7 days was mainly due to an increase in MACE events
which may also be explained by study design. The same statistical considerations apply for MACE
events for all-cause mortality. Some patients with sudden death on treatment had underlying
cardiovascular risk factors. It was pointed out that the intermittent increase in heart rate about 2 – 4
hours after drug intake might be of concern for patients at increased cardiovascular risk due to
coronary artery disease (see safety section below). Albeit the changes in heart rate were generally
modest and similar to those seen with other medicinal products approved for PAH the applicant agreed
to include contraindications in place for prostacyclin analogues (e.g. severe coronary artery disease,
status post myocardial infarction, unstable angina).
The main study result was consistent in all of the subgroups investigated. Only in Asian patients and in
Asia as a geographical region there was no treatment effect. In North America the treatment effect
was numerically lower than in the other regions. Irrespectively of the regional differences, the results
do not raise concerns for an application in the EU. Only few Black patients were included. Albeit
numerically in favour of selexipag, only limited conclusions can be drawn on B/R in black patients.
The clinical relevance of the effect on the primary endpoint can further be assessed based on the
results of the secondary endpoints. 6 MWT: There was a mean decrease from baseline to week 26 by
53 m in the selexipag group and by 66 m in the placebo group. Median change was + 4.0 vs. – 9.0 m,
respectively, indicating that many patients were largely in a stable condition over 26 weeks. The
treatment effect on the 6MWD in treatment naïve patients (difference of +34 m vs. placebo at the pre-
defined timepoint of 6 months (99% CI: 10.0; 63.0, p = 0.0002)) was within the range of what has
been observed with other medicinal products previously approved in the EU. As expected, the effect
was smaller in patients pretreated with ERA, PDEi or ERA+ PDEi (location shift -1 (-38.0; 28.0 m),
+12.0 (-8.0; 33.0m), and +6.0 (-14.0; 24.0 m), respectively). In patients with FC III/(IV) the
difference was larger (+17.0 (-1.0; 36m) than in patients with FC (I)/II (+5.0 (-8.0; 19.0 m)).
Taking into consideration the clinically relevant effect in treatment naive patients that was in the range
of other medicinal products approved for PAH and the well known observation that the effect on the 6
MWD is less pronounced in pretreated patients, the moderate mean overall effect on 6-MWD observed
in the study is mainly related to the high number of pretreated patients included in the study .
Due to low numbers one should be cautious not to over interpret the negative results in the elderly (≥
65 years), in North America, and in Black patients.
For the reasons of internal consistency, it should be demonstrated that an improvement in 6MWD is
correlated with not developing the main study outcome "morbidity/mortality". In this respect, the
applicant was requested to provide: An analysis of responders in 6MWD, defined in absolute and
relative terms as: i) Improvement > 30 m from baseline at study endpoint; ii) Improvement > 15%
from baseline at study endpoint. The applicant has provided the analysis. The effect compared to
baseline depended largely on the imputation of missing values, but the effect as compared to placebo
was unaffected.
There was no clinically relevant effect of selexipag on overall quality of life and on breathlessness
as measured by the CAMPHOR scale. This finding is not fully understood since the clear benefit with
regard to morbidity events would be expected to translate into improved QoL However, although the
CAMPHOR scale has been validated in small populations in different regions, it is currently not known
whether it is sensitive to changes in QoL. Therefore, the lack of impact of selexipag on QoL as
measured by the CAMPHOR questionnaire does not invalidate the beneficial effects of selexipag on
morbidity events.
For NT-proBNP levels median improvements on therapy vs. placebo were small.
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There was no correlation between maintenance dose and the primary endpoint outcome at least for
patients with typical AEs. This is consistent with the assumption that, on an individual level, tolerability
correlates with efficacy. For patients without AEs typical for prostacyclin analogues efficacy was
questionable for the lowest dose range. It may be appropriate that these patients try to increase their
dose during therapy.
2.5.4 Conclusions on clinical efficacy
In summary, a statistically significant and clinically relevant benefit as measured by the primary
endpoint has been demonstrated for patients with PAH in FC II and III, on baseline therapy or
treatment naïve. The result was consistent for almost all of the relevant subgroups, except Asian
patients and Asia and North America as region. Patients with idiopathic/hereditary PAH or connective
tissue disease in FC stages II – III and patients with PAH associated with simple corrected congenital
heart disease were sufficiently represented in the study to be reflected in the wording of an indication.
The analysis of the results for all-cause mortality is challenging. At the primary analysis timepoint
EOT+7d, selexipag appeared to have a negative effect on mortality as the primary endpoint
component. This finding can be explained statistically by informative censoring. On the other hand, the
analysis up to study closure in the FAS suggested a neutral effect and mathematical models which take
into account cross-over even indicated an up to 25% reduction in mortality.These models have
limitations due to assumptions that have to be made and should be interpreted with caution.
The finding of increased all-cause mortality as primary endpoint event was mainly observed in patients
in FC II and in those with better cardiac functioning and was paralleled by an increase in MACE events
that also may be related to informative censoring. The safety data did not indicate a specific concern
related to patients in FC II and there was no plausible explanation for a risk in patients in FC II and
better cardiac functioning that would not be relevant for more vulnerable patients at a more advanced
stage of PAH. Cross study comparisons, albeit to be taken with caution, indicated that the mortality
rate in the selexipag arm in FC II was largely within the expected range, whereas mortality in the
placebo arm (FCII) was low.
Overall, CHMP considered that the finding of increased mortality as a primary endpoint event is most
likely due to informative censoring and/or a chance finding. This assumption is supported by the
following considerations: a) selexipag exerted beneficial effects on morbidity endpoints in patients with
PAH and morbidity events were shown to increase the risk of dying, b) selexipag is an IP receptor
agonist with the typical adverse event profile of the prostacyclin/prostacyclin analogues known class of
PAH medications; prostacyclins are not suspected to be associated with an increased risk of mortality
c) the increase in heart rate after each dose is generally modest and transient and in the range of
other vasodilatory drugs approved for PAH, d) no specific/unique safety issue could be identified that
could explain an increase in mortality, e) any putative safety issue leading to increased mortality would
be more likely to become evident in PAH patients with deteriorated health condition as opposed to
patients in FCII and better cardiac functioning. Reference is also made to the safety section of this
report.
The overall effect of selexipag on the 6 MWT appeared to be moderate when compared to the effects
observed with non-prostacyclin medicinal products in a cross study comparison. However, the effect in
treatment naïve patients was in the range of what has previously been observed and accepted as
clinically relevant. Therefore, the mean effect was largely driven by the high number of patients (about
80%) on baseline therapy. It is well known that only smaller effects can be expected in these patients.
There was no improvement in quality of life as measured by the CAMPHOR scale. At present, it cannot
be finally decided whether this is due to a low sensitivity of the test used or indicates that the clinically
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relevant benefits of selexipag on morbidity events do not translate into improvements in the categories
investigated by the test.
Although the beneficial effects might be regarded as moderate, they are clinically relevant. As most
patients (about 80%) in GRIPHON received selexipag on top of baseline therapy with ERAs and/or
PDE5-inhibitors, a second line indication is considered appropriate in order not to withhold therapeutic
use of these drugs that have an established clinical benefit demonstrated over years in large numbers
of patients.
2.6 Clinical safety
Safety information is mainly contributed by completed pivotal Phase 3 study AC-065A302 (GRIPHON)
in the PAH indication. This study has 1152 patients in its safety data set. Beside this pivotal trial, only
a few small Phase 2 trials with 26 to 43 patients per study were performed, in the PAH and also in the
CTEPH (chronic thromboembolic pulmonary hypertension) indication. Thus, safety evaluation is mostly
based on the GRIPHON trial. GRIPHON has an ongoing, uncontrolled extension phase (i.e. all patients
are treated with selexipag, no comparator is included).
An independent Critical Event Committee (CEC) adjudicated all reported morbidity/mortality (MM)
events. The CEC was blinded to the patient’s study treatment allocation and to the occurrence of
typical prostacyclin-associated adverse events (AEs). The CEC comprised 3 clinical experts who had
experience and expertise in the management of patients within this disease area, and experience in
the monitoring of randomized clinical trials. The CEC members were not involved as investigators in
the GRIPHON study.
Patient exposure
Exposure is described below for the double-blind period of the GRIPHON study. In the phase 1 and
phase 2 studies patient exposure was comparably low. In study AC-065A303 (open-label extension of
GRIPHON), median duration of study treatment (up to 10 March 2014) was 37.2 weeks (range: 0.9–
160.0 weeks), with 34.4% of patients (75/218) receiving study treatment for a cumulative duration of
at least 1 year.
GRIPHON study, double blind period
Median duration of study treatment in study AC-065A302 was 70.7 weeks (range: 0.3–216.7 weeks) in
the selexipag group compared to 63.7 weeks (range: 0.7–192.0 weeks) in the placebo group, with
63.8% and 62.6% of patients in the respective groups receiving study treatment for a cumulative
duration of at least 1 year. The proportion of patients who received study treatment for a cumulative
duration of at least 2 years was 31.3% in the selexipag group and 27.4% in the placebo group.
Thus, the mean duration of treatment was close to one and a half year in the selexipag group, and the
majority of patients were treated for more than one year. For further details see table below.
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Table 12-1 of Study Report: Duration of study treatment in AC-065A302, SAF
Selexipag
Placebo
N=575
N=577
Duration of study treatment (weeks)
Non-missing
575
577
Mean
76.4
71.2
Standard deviation
50.45
48.32
Min, Q1
0.3, 32.0
0.7, 28.6
Median
70.7
63.7
Q3 , Max
117.1, 216.7
107.1, 192.0
Cumulative duration of study treatment [n (%)]
Non-missing
575
577
At least 8 weeks
527 (91.7%)
545 (94.5%)
At least 16 weeks
494 (85.9%)
494 (85.6%)
At least 26 weeks
457 (79.5%)
444 (76.9%)
At least 52 weeks
367 (63.8%)
361 (62.6%)
At least 78 weeks
259 (45.0%)
235 (40.7%)
At least 104 weeks
180 (31.3%)
158 (27.4%)
At least 130 weeks
107 (18.6%)
94 (16.3%)
At least 156 weeks
43 ( 7.5%)
31 ( 5.4%)
At least 182 weeks
7 ( 1.2%)
4 ( 0.7%)
At least 208 weeks
1 ( 0.2%)
0
Of the 575 selexipag-treated patients in study AC-065A302, 28.3% received selexipag at an individual
maintenance dose (IMD) of 1600 μg bid (i.e., the maximum selexipag dose allowed in the study). In
the placebo group, the highest number of tablets corresponding to the 1600 μg bid IMD was achieved
by 67.5% of patients. For details see table below.
Table 15-38 of study report: Individual maintenance dose of selexipag and
placebo in AC-065A302, FAS
Selexipag
Placebo
N=574
N=582
n (%)
n (%)
bid dose (or placebo equivalent)
0 mcg
14 ( 2.4%)
9 ( 1.5%)
200 mcg
68 (11.8%)
15 ( 2.6%)
400 mcg
65 (11.3%)
18 ( 3.1%)
600 mcg
62 (10.8%)
20 ( 3.4%)
800 mcg
82 (14.3%)
21 ( 3.6%)
1000 mcg
35 ( 6.1%)
27 ( 4.6%)
1200 mcg
42 ( 7.3%)
20 ( 3.4%)
1400 mcg
41 ( 7.1%)
55 ( 9.5%)
1600 mcg
163 (28.4%)
393 (67.5%)
Other than per
protocol dosing
regimen
2 ( 0.3%)
4 ( 0.7%)
IMD is defined as the selexipag or placebo bid dose to which each patient was
exposed for the longest duration in the maintenance period, or, for patients who did
not enter maintenance, as the highest tolerated selexipag or placebo bid dose to
which each patient was exposed during the titration period.
Adverse events
GRIPHON study, double blind period (AC-065A302)
A total of 98.3% and 96.9% of patients in the selexipag and placebo groups, respectively, had at least
1 AE in study AC-065A302 (i.e. GRIPHON, double blind period). The Applicant defined certain AEs as
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“prostacyclin-associated AEs” which included pain in various defined locations, flushing and several
gastrointestinal effects. These AEs were also defined as AEs of special interest. These prostacyclin-
associated AEs, together with the related AEs abdominal pain and neck pain, were the most frequently
reported AEs and had markedly higher frequencies in the selexipag group compared to the placebo
group. Other salient AEs reported more frequently on selexipag compared to placebo included
hypotension (5.0% vs 3.1%), anaemia (8.3% vs 5.4%), hyperthyroidism (1.4% vs. 0%) and acute
renal failure (2.4% vs 1.2%).
On the level of SOC (System Organ Class), skin and subcutaneous tissue disorders revealed an
imbalance. Respective events were reported for 19.7% of patients in the selexipag group compared to
15.8% in the placebo group. This difference was mainly driven by rash (4.5% selexipag, 2.8%
placebo) and erythema (2.3% vs. 1.4%). Furthermore, Eye disorders were reported for 11.0% of
patients in the selexipag group compared to 8.0% in the placebo groups. This difference was mainly
driven by the PT “Eye Pain” (1.6% vs. 0.3%).
On the other hand, PAH (worsening) and right ventricular failure were reported less frequently in the
selexipag group (21.9% and 8.0% of patients, respectively) compared to the placebo group (35.7%
and 10.1%, respectively). Similarly, other manifestations of underlying PAH disease were also reported
less frequently in the selexipag group compared to placebo: dyspnoea (16.0% vs 21.0%), peripheral
oedema (13.9% vs 18.0%), and syncope (6.4% vs 8.8%).
Taken together, most of the AEs which were more frequent in the selexipag group are most likely
related to the PD effect of selexipag (the so-called prostacyclin-associated AEs as well as hypotension).
Beside these, salient differences between selexipag and placebo were observed for anaemia,
hyperthyroidism and acute renal failure. These conditions are further discussed as AEs of special
interest below.
Nasopharyngitis and influenza were also more frequent with selexipag, but infections and infestations
in total were well balanced between selexipag and placebo. Thus, there is no hint that selexipag affects
the immune system.
Table 12-4 of Study Report: Treatment-emergent AEs in study AC-065A302 sorted by
difference in incidence (at least 1.0%) between selexipag and placebo, SAF
Selexipag
Placebo
Selexipag
minus
Placebo
Preferred Term
N=575
N=577
n
%
n
%
Patients with at least
one AE
565
98.3%
559
96.9%
1.4%
HEADACHE
375
65.2%
189
32.8%
32.5%
DIARRHOEA
244
42.4%
110
19.1%
23.4%
PAIN IN JAW
148
25.7%
36
6.2%
19.5%
NAUSEA
193
33.6%
107
18.5%
15.0%
MYALGIA
92
16.0%
34
5.9%
10.1%
VOMITING
104
18.1%
49
8.5%
9.6%
PAIN IN EXTREMITY
97
16.9%
46
8.0%
8.9%
FLUSHING
70
12.2%
29
5.0%
7.1%
ARTHRALGIA
62
10.8%
44
7.6%
3.2%
ANAEMIA
48
8.3%
31
5.4%
3.0%
ABDOMINAL PAIN
48
8.3%
33
5.7%
2.6%
DECREASED APPETITE
34
5.9%
19
3.3%
2.6%
PAIN
18
3.1%
3
0.5%
2.6%
NASOPHARYNGITIS
75
13.0%
63
10.9%
2.1%
HYPOTENSION
29
5.0%
18
3.1%
1.9%
DYSPEPSIA
25
4.3%
14
2.4%
1.9%
RASH
26
4.5%
16
2.8%
1.7%
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WEIGHT DECREASED
17
3.0%
8
1.4%
1.6%
NECK PAIN
15
2.6%
6
1.0%
1.6%
HYPERTHYROIDISM
8
1.4%
0
1.4%
ASTHENIA
31
5.4%
24
4.2%
1.2%
ABDOMINAL DISCOMFORT
21
3.7%
14
2.4%
1.2%
RENAL FAILURE ACUTE
14
2.4%
7
1.2%
1.2%
BONE PAIN
9
1.6%
2
0.3%
1.2%
EYE PAIN
9
1.6%
2
0.3%
1.2%
PYREXIA
23
4.0%
17
2.9%
1.1%
INFLUENZA
20
3.5%
14
2.4%
1.1%
MUSCULOSKELETAL PAIN
18
3.1%
12
2.1%
1.1%
NASAL CONGESTION
17
3.0%
11
1.9%
1.1%
HOT FLUSH
14
2.4%
8
1.4%
1.0%
BURNING SENSATION
6
1.0%
0
1.0%
Intensity of the AEs
In study AC-065A302, AEs of mild and moderate intensity were reported for 8.2% and 41.0% of
patients, respectively, in the selexipag group and 8.8% and 42.8% of patients, respectively, in the
placebo group. Severe intensity AEs were reported for 49.0% and 44.9% of patients in the selexipag
and placebo groups, respectively. The most frequently reported severe AE was PAH (14.4% selexipag,
21.0% placebo).
Investigator-attributed relationship of adverse events to study treatment
In study AC-065A302, 89.6% of patients in the selexipag group had at least 1 AE which was
considered by the investigator to be treatment-related compared to 56.7% in the placebo group.
Prostacyclin-associated AEs were the events most frequently considered by the investigator to be
treatment-related. Other individual PT AEs considered treatment-related and reported more frequently
in the selexipag group compared to the placebo group included decreased appetite (3.5% vs 1.4%),
pain (2.4% vs 0.5%), and decreased weight (1.0% vs 0%).
GRIPHON study, open label period (AC-065A303)
Of the 218 patients who were enrolled and received selexipag in study AC-065A303, 209 (95.9%) had
at least 1 AE. Similar to AC-065A302, prostacyclin-associated AEs (i.e., headache, diarrhoea, jaw pain,
nausea, vomiting, pain in extremity, myalgia, arthralgia, and flushing) were the most frequently
reported AEs in AC-065A303. PAH (worsening) and right ventricular failure were reported for 25.7%
and 16.5% of patients, respectively. Other frequently reported AEs included peripheral oedema
(11.5%), anaemia (5.5%), hypotension (4.6%), and decreased appetite (4.1%). For further AEs see
table below. No placebo arm was included in this open-label period.
Thus, AEs probably related to prostacyclin physiology were also frequent in the uncontrolled extension
period of the GRIPHON study. Other events can be related to the underlying disease or accompanying
medication. This study period gives no hint for undesired effects of selexipag that were not yet
detected in the double blind period.
Table 12-5: Treatment-emergent AEs in study AC-065A303 sorted by PT
incidence (at least 3%), SAF (subset treated in study AC-065A303)
Selexipag
Preferred Term
N=218
n
%
Adverse events
Patients with at least one AE
209
95.9%
HEADACHE
119
54.6%
DIARRHOEA
78
35.8%
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PULMONARY ARTERIAL HYPERTENSION
56
25.7%
PAIN IN JAW
46
21.1%
NAUSEA
44
20.2%
RIGHT VENTRICULAR FAILURE
36
16.5%
VOMITING
31
14.2%
OEDEMA PERIPHERAL
25
11.5%
PAIN IN EXTREMITY
25
11.5%
MYALGIA
22
10.1%
ARTHRALGIA
21
9.6%
DIZZINESS
18
8.3%
DYSPNOEA
18
8.3%
FLUSHING
18
8.3%
COUGH
14
6.4%
UPPER RESPIRATORY TRACT INFECTION
14
6.4%
NASOPHARYNGITIS
13
6.0%
ANAEMIA
12
5.5%
BRONCHITIS
12
5.5%
FATIGUE
10
4.6%
HYPOTENSION
10
4.6%
ABDOMINAL PAIN UPPER
9
4.1%
DECREASED APPETITE
9
4.1%
SYNCOPE
9
4.1%
ASCITES
8
3.7%
PNEUMONIA
8
3.7%
URINARY TRACT INFECTION
8
3.7%
ABDOMINAL PAIN
7
3.2%
CONSTIPATION
7
3.2%
EPISTAXIS
7
3.2%
HAEMOPTYSIS
7
3.2%
HYPOKALAEMIA
7
3.2%
PALPITATIONS
7
3.2%
PYREXIA
7
3.2%
AEs of special interest
The AEs of special interest included those expected to be observed with selexipag based on its
mechanism of action i.e., prostacyclin-associated AEs, hypotension, and haemorrhage (also of
increased risk in PAH, particularly in patients receiving anticoagulants and anti-platelet agents) and
AEs of potential risk identified from preclinical studies with selexipag i.e., eye disorders (retinal
vasculature impairment). Furthermore, malignancies and signs of drug-induced liver injury were
regarded as AEs of special interest. In addition, AEs which were found to be more frequent with
selexipag than with placebo were discussed by the Applicant in further detail, namely anaemia, renal
failure (including other renal disorders for completeness) and hyperthyroidism.
In case of hypotension, a mechanistic link is likely based on theoretical considerations (prostacyclin-
mediated vasodilation). Reassuringly, the incidence of serious hypotension events was balanced
between selexipag and placebo.
For renal failure, a causal relationship to selexipag treatment remained unclear. Not all events were
regarded serious; e.g. temporal worsening of chronic renal failure was considered non-serious. For
serious events of acute renal failure, the imbalance was smaller (10 patients with selexipag vs. 7
patients with placebo).
Malignancies and MACE are described in more detail in the following. For the other AEs of special
interest the closer analysis did not reveal new insights and is therefore not presented. No relevant
differences between selexipag and placebo were detected for haemorrhage.
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Malignancies
Malignancy AEs were reported for 11 patients (14 AEs) in the selexipag group versus 4 patients (4
AEs) in the placebo group. All events were considered by the investigator to be unrelated to study
drug. The events were reported as serious in 7 patients (8 events) in the selexipag group and 4
patients (4 events) in the placebo group. There was a salient imbalance in light-dependent skin
tumours (basalioma and keratoacanthoma) in the selexipag vs. placebo group (five tumours in four
patients of the selexipag group, none in the placebo group).
PAH can be associated with autoimmune disease so that some patients received immunosuppressant
medication prior or during the study. However, no relevant differences between the selexipag and the
placebo group become obvious.
It is known that sunlight exposure can play a role in the formation of the types of skin tumours which
were observed in the selexipag group. Simultaneously, selexipag was found to be potentially
phototoxic in an in-vitro screening test (see Non-clinical AR). The Applicant aimed to confirm or
exclude phototoxicity of selexipag in a dedicated Phase 1 study AC-065-102 (see Pharmacology section
for details).
However, this study is not informative since the positive control did not yield the expected results.
Cardiovascular events
There was a numerical imbalance in serious and total Major Adverse Cardiovascular Events (MACE) in
the selexipag vs. the placebo group in the GRIPHON study (double blind period), in disfavour of
selexipag. A mechanistic link to selexipag action is not immediately obvious since prostacyclin inhibits
platelet aggregation which could even have a protective effect. The analysis of MACE is summarized in
the table below. The overall proportion of patients with such events was 2.4% in the selexipag group
and 1.4% in the placebo group. Corrected for exposure, the average annualized event rate was 0.015
and 0.010 for selexipag and placebo, respectively. No specific leading cause of MACE was identified;
see the two following tables for details.
Table 57 : Summary of MACE AEs in the DOUBLE BLIND, placebo-controlled PAH safety
analysis set from study AC-065A302 (Pool 1)
Selexipag (N=575)
Placebo (N=577)
n
%
n
%
Patients with at least one AESI
14
2.4%
8
1.4%
Patients with at least one AESI leading to
discontinuation
8 1.4% 2 0.3%
Patients with at least one serious AESI
14
2.4%
7
1.2%
Patients with at least one AESI with a fatal
outcome
10 1.7% 6 1.0%
Average annualized event rate
0.016
0.010
Number of recurrent AESI
14
8
Patient-years of observation
851.529
794.505
Serious adverse events and deaths
Deaths
The numbers of fatal events as a component of the primary endpoint were 25 (4.4%) and 16 (2.7%) in
the selexipag and placebo groups, respectively. However, due to the competing nature of
morbidity/mortality events considered for the primary endpoint, informative censoring takes place, and
these numbers should be interpreted with caution (see Efficacy and B/R part of this report for detailled
explanation and discussion of informative censoring).
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Overall, a total of 46 deaths (8.0%) and 37 deaths (6.4%) in the selexipag and placebo groups,
respectively, were reported up to EOT + 7 days. Among these, a similar proportion (71.7% vs 73.0%)
in the selexipag and placebo group, respectively, were adjudicated as PAH-related by the CEC. At
Study closure, the number of deaths was similar in the selexipag and placebo groups (100 [17.4%]
and 105 [18.0%] respectively). The proportion of patients who died due to PAH was 12.2% and 14.3%
in the selexipag and placebo groups, respectively. For further details see table below.
Table 12-7 of study report: Summary of deaths in AC-065A302 Full analysis set
Selexipag N = 574 n (%)
Placebo N = 582 n (%)
Deaths as the first event up
to EOT + 7 days
28 (4.9)
18 (3.1)
All deaths up to EOT + 7
days
46 (8.0)
37 (6.4)
Death due to PAH
33 (71.7)
27 (73.0)
Death not due to PAH
13 (28.3)
10 (27.0)
All deaths up to Study
closure
100 (17.4)
105 (18.0)
Death due to PAH
70 (12.2)
83 (14.3)
Death not due to PAH
30 (5.2)
22 (3.8)
The treatment duration was somewhat longer in selexipag vs. placebo patients (mean 76.4 vs. 71.2
weeks, see Section 4.2 “Patient exposure” above). The hazard ratio for mortality for the treatment
period was 1.17, as stated in the Kaplan-Meier plot below.
Figure 1-87 Appendix 2: Kaplan-Meier estimates of time from randomization to CEC
confirmed death up to AC-065A302 EOT + 7 days, FAS
Most of the fatal events were regarded as cardiac death (38 of 46 in the selexipag group and 29 of
37 in the plc group).
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The imbalance in overall mortality and cardiac deaths was restricted to patients in FC I/II, see table
below.
Table 3 of Response Document: Adjudicated cause of death up to EOT + 7 days (blinded
adjudication by independent cardiologist and CEC) by WHO FC at baseline, AC-065A302, FAS
CEC = Critical Event Committee; EOT = End of treatment; FAS = Full analysis set; FC = functional
class
Otherwise, major deviations of a subgroup HR from the all patient HR were only observed for small
subgroups in which, due to the low patient number, a high degree of uncertainty resulted.
The Applicant also provided a Kaplan-Meier plot (see below) of survival restricted to patients with
“typical PAH”, whereby Typical PAH is defined as PAH in patients who had no co-morbidity that might
have introduced a doubt on the aetiology of PAH. It turned out that this large subgroup of patients also
had a higher mortality in the selexipag group; the HR was 1.28 and thereby numerically even higher
than in all patients (HR 1.17).
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Figure 1-112 Appendix 2: Time from randomization to CEC-confirmed death up to 7 days
after last study drug intake in the AC-065A302 Treatment Period in patients with typical
PAH according to the blinded expert review - Kaplan-Meier estimates, FAS patients with
typical or consistent PAH
An independent analysis investigated the influence of several baseline factors on mortality. A
significant association was found for cardiac index (CI), whereby the interaction was complex. The
Kaplan-Meier plot below visualises mortality over time for patients with low (25th percentile, marked
"Q1" in the figure) and high (75th percentile, marked "Q3" in the figure) CI, having received selexipag
or placebo. The placebo group meets the expectations in that mortality was higher with low cardiac
index (Q1) than with high CI (Q3). With selexipag, mortality decreased in the low-CI group but clearly
increased in the high-CI group. The reason for this effect in the high-CI-group is not clear.
Figure 4 -response Document: Estimated mortality up to Study closure by treatment group
Increased mortality with higher CI (>Q3) is also clearly visible in the Forest plot analysis shown below.
Figure 3 of the Response Document: Time to death up to EOS, selexipag vs placebo, by
quartiles of cardiac index at baseline, AC-065A302, FAS
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In search for potential explanations of the observed numerically higher mortality with selexipag up to
EOT+7d, the applicant performed two independent mathematical modelling approaches (for details
see section 3.4.5 Clinical Efficacy). Assuming selexipag to have a beneficial effect non-fatal events and
a neutral effect on mortality, the results of the mathematic models fitted the observed difference in
deaths very well. In particular, the simulation in the first model showed on average 38 deaths for
placebo and 46 deaths for selexipag, compared to the observed 37 and 46 deaths, respectively. The
probability of observing more deaths with selexipag compared to placebo was 79% and of observing
an excess of 9 or more deaths was 45%. In the second model, the likelihood of observing more
deaths in the selexipag arm up to EOT+7d was also high, ranging from 60–81%. The expected
difference ranged from 3.0 to 7.8, and the probability of observing a difference of 9 or more deaths
between treatment arms up to EOT+7d was 26–47%. This model considered three scenarios of
acceleration of the death process by an endpoint event. Hence, the probabilities are given as ranges
covering the three scenarios.
SAEs
In AC-065A302, 43.8% and 47.1% of patients in the selexipag and placebo groups, respectively, had
at least 1 SAE (see table below), i.e. SAEs were numerically lower with selexipag than with placebo.
PAH worsening and right ventricular failure were the most frequently reported SAEs, and both were
reported at lower frequencies in the selexipag group (14.4% and 5.9%, respectively) compared to the
placebo group (22.0% and 7.1%, respectively). Other SAEs reported at lower frequencies in the
selexipag group included pneumonia (3.0% selexipag, 4.3% placebo) and syncope (1.7% selexipag,
3.5% placebo). The SAE “right ventricular failure” was less frequent in the selexipag group which is
well in line with the efficacy finding of slowing of PAH progression
Table 12-8: Treatment-emergent SAEs in study AC-065A302 sorted by PT incidence, SAF
Selexipag
Placebo
Preferred Term
N=575
N=577
n
%
n
%
Adverse events
Patients with at least one SAE
252
43.8%
272
47.1%
Number of SAEs
513
515
PULMONARY ARTERIAL
HYPERTENSION
83
14.4%
127
22.0%
RIGHT VENTRICULAR FAILURE
34
5.9%
41
7.1%
PNEUMONIA
17
3.0%
25
4.3%
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DYSPNOEA
17
3.0%
13
2.3%
SYNCOPE
10
1.7%
20
3.5%
ATRIAL FIBRILLATION
7
1.2%
4
0.7%
CHEST PAIN
6
1.0%
6
1.0%
RENAL FAILURE ACUTE
6
1.0%
6
1.0%
BRONCHITIS
6
1.0%
4
0.7%
HAEMOPTYSIS
5
0.9%
5
0.9%
ABDOMINAL PAIN
5
0.9%
4
0.7%
SUDDEN DEATH
5
0.9%
4
0.7%
ANAEMIA
5
0.9%
3
0.5%
SYSTEMIC LUPUS
ERYTHEMATOSUS
5
0.9%
1
0.2%
EPISTAXIS
4
0.7%
4
0.7%
LOWER RESPIRATORY TRACT
INFECTION
4
0.7%
4
0.7%
PULMONARY EMBOLISM
4
0.7%
3
0.5%
RESPIRATORY TRACT INFECTION
4
0.7%
3
0.5%
UPPER RESPIRATORY TRACT
INFECTION
4
0.7%
3
0.5%
LUNG INFECTION
4
0.7%
2
0.3%
ROAD TRAFFIC ACCIDENT
4
0.7%
2
0.3%
The percentage of patients with AEs with fatal outcome was larger in the selexipag than in the placebo
group (on-treatment), see table below. This is in line with the numerically increased mortality
described above, subsection “Deaths”. PAH or cardiopulmonary failure as causes of death were more
frequently reported with selexipag than with placebo, despite an overall slowed disease progression.
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Table 15-199 (shortened): Treatment-emergent SAEs in study AC-065A302 with fatal
outcome sorted by PT incidence in the selexipag group, SAF (EOT + 7 days)
Selexipag
Placebo
Preferred Term
N=575
N=577
n
%
n
%
Patients with fatal SAE
49
8.5%
41
7.1%
Number of fatal SAEs
73
64
PULMONARY ARTERIAL HYPERTENSION
19
3.3%
16
2.8%
RIGHT VENTRICULAR FAILURE
7
1.2%
6
1.0%
SUDDEN DEATH
5
0.9%
4
0.7%
CARDIOPULMONARY FAILURE
3
0.5%
1
0.2%
ACUTE RIGHT VENTRICULAR FAILURE
2
0.3%
3
0.5%
RENAL FAILURE ACUTE
2
0.3%
3
0.5%
CARDIO-RESPIRATORY ARREST
2
0.3%
2
0.3%
PNEUMONIA
2
0.3%
2
0.3%
CARDIAC ARREST
2
0.3%
1
0.2%
ROAD TRAFFIC ACCIDENT
2
0.3%
1
0.2%
VENTRICULAR FIBRILLATION
2
0.3%
0
The adjudication of death cases was made separately by the CEC and by an external expert
cardiologist. Combining the adjudications identified 7 cases of sudden cardiac death (6 selexipag, 1
placebo) not related to PAH (up to EOT + 7 days). Most of the six patients in the selexipag group had
pre-existing CV disease beyond PAH.
Laboratory findings
Haematology
Mean absolute changes from baseline to regular visits in haemoglobin ranged from −3.4 to −0.6 g/L in
the selexipag group compared to −0.6 to 3.0 g/L in the placebo group of the GRIPHON study. Mean
absolute change from baseline to regular visits in platelet count ranged from 3.1 to 9.7 GI/L in the
selexipag group compared to −4.6 to 2.2 GI/L in the placebo group. There were no changes from
baseline in mean haematocrit, erythrocyte and leukocyte counts in the two groups. However, markedly
decreased Hb was more frequently reported as an AE in the selexipag as compared to the placebo
group (<80 g/L, 1.3% vs.0.7%; <100 g/L, 8.8% vs. 5.0%). There was also an increased frequency of
reported decreases in leukocyte count in the selexipag group (<2.0 G/L, 0.9% vs. 0.2%; <3.0 G/L,
5.0% vs. 2.0%).
Serum Chemistry
There were 2.5% of patients in the selexipag group and 1.4% in the placebo group reporting
decreased potassium to <3.0 mmol/L. No relevant differences between selexipag and placebo in mean
potassium level were observed. There was one patient in the selexipag group who had study drug dose
reduction due to hypokalaemia. Otherwise no relevant imbalances between the groups disfavouring
selexipag were observed.
Vital signs
Heart rate and ECG
At the Month 12 visit, an ECG at 2 and 4 h post-dose was performed. Median HR was 74.0 and 72.0
bpm in the selexipag and placebo groups, respectively, at pre-dose at Month 12. The mean change
from pre-dose in HR at 2 h post-dose was 5.4 bpm and 2.1 bpm for selexipag and placebo,
respectively. At 4 h post-dose, the mean change from pre-dose value was smaller than after 2 hours
for selexipag, 3.7 bpm. Changes in the PR interval were consistent with the observed HR changes. No
meaningful changes in QRS duration and the QTcF interval were observed at 2 and 4 h post-dose ECG
recordings.
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Categorical heart rate analysis of the GRIPHON trial data (see table below) revealed a higher
percentage of patients with a HR increase of >10, >15 or >20 bpm 2 hours after dosing in the
selexipag compared to the plc group (see Table 18 below).
Table 18 from the Response Document: Categorical change in heart rate post-dose vs pre-
dose at Month 12 (ECG), AC-065A302, SAF
*Selexipag vs. placebo for increased heart rate
Blood pressure
A higher percentage of patients in the selexipag than in the placebo group of GRIPHON (double blind
period) revealed low SBP (<90 mmHg), 9.7% vs. 6.7%, in line with the observed increased incidence
in hypotension. No meaningful changes in mean blood pressure were observed in GRIPHON. In the
selexipag group, mean changes from baseline in SBP ranged from -2.0 to 1.5 mmHg compared to -1.3
to 0.0 mmHg in the placebo group; DBP: -1.6 to -0.1 mmHg vs. -1.1 to 0.3 mmHg.
Bone turnover markers
Because of bone findings in animals (increased ossification in dogs, characterized by periosteal bone
formation and increased thickness and numbers of trabeculae), bone turnover markers were assessed
in study AC-065A302 (i.e. double blind period of GRIPHON). Mean absolute changes from baseline in
bone specific alkaline phosphatase and carboxyterminal telopeptide showed no consistent pattern in
either group. Thus, no hints for bone effects in humans were detected. The Applicant also had
performed mechanistic studies in animals which make a dog-specific effect likely.
Safety in special populations
Age: The safety analysis set comprised 476 patients aged < 65 years treated with selexipag (709
patient-years) vs 470 treated with placebo (638 patient-years), and 91 patients aged 65–74 years
treated with selexipag (116 patient-years) vs 102 treated with placebo (137 patient-years). The
number of patients ≥ 75 years old was low (8 selexipag, 5 placebo) and insufficient to allow
meaningful evaluation of AEs in this age group. The overall AE frequency was 97.5% and 100% in the
selexipag group and 97.0% and 96.1% in the placebo group for patients aged < 65 years and 65–74
years, respectively. The pattern of AEs was generally similar in patients aged < 65 years and in those
aged 65–74 years, although some differences in the frequency of individual AEs was observed. A
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higher frequency of prostacyclin AEs leading to discontinuation of selexipag treatment was reported for
patients aged between 65 and 75.
Regarding other special populations, the Applicant provided AE listings for several demographic factors,
type of PAH and background medication. No special concerns became obvious. No safety information
on patients with liver or kidney disease was provided.
Patients with relevant renal or hepatic impairment were rare in the GRIPHON study so that safety
evaluation of these subgroups is not possible.
Immunological events
In the GRIPHON study, double blind period, there were three cases (0.5%) of hypersensitivity reported
in the selexipag group vs. four cases (0.7%) in the placebo group. In total, immune system disorders
were reported in 1.9% vs. 3.8% of patients (selexipag vs. placebo) in this study.
Safety related to drug-drug interactions and other interactions
The Applicant provided AE listings stratified for the different accompanying PAH treatments. No marked
differences according to accompanying PAH medication can be detected. The AE profile was similar
under all conditions, with an increase of gastrointestinal AEs, pain in various locations and
rash/flushing increased in the selexipag groups vs. placebo. Interaction was more closely studied for
hypotension. The triple combination of selexipag, ERA and PDE5i produced the highest rate of
hypotension.
Discontinuation due to AES
A total of 31.7% of patients in the selexipag group had at least 1 AE leading to discontinuation of study
drug in study AC-065A302 compared to 37.1% in the placebo group. The most frequently reported AE
leading to discontinuation of study drug was PAH worsening (13.6% selexipag, 23.4% placebo). The
proportion of patients who discontinued due to right ventricular failure was 2.4% in the selexipag
group and 4.0% in the placebo group. Hence, a marked difference in discontinuation due to PAH was
observed in favour of selexipag. This again indicates that selexipag can influence PAH progression
positively. Conversely, more patients in the selexipag group than in the placebo group discontinued
due to presumably prostacyclin-related effects. The total discontinuation rate was higher in the placebo
group.
2.6.1 Discussion on clinical safety
The safety information is mainly based on the double-blind, placebo-controlled treatment period of the
pivotal phase 3 study GRIPHON. Nearly all patients had at least one AE in the selexipag as well as in
the placebo group. However, there was a set of characteristic AEs which were markedly more frequent
with selexipag than with placebo. These AEs included various gastrointestinal (GI) symptoms, pain at
various locations and flushing. Furthermore, mean heart rate was increased for a few hours after each
administration of selexipag (mean 3.3 bpm vs. placebo) whereas mean systemic blood pressure was
hardly affected; however, events of hypotension were more frequent with selexipag than with placebo.
All these mentioned signs and symptoms are in line with the PD action of selexipag, i.e. activation of
the IP receptor. The Applicant therefore used the term “prostacyclin-associated AEs” to describe this
set of AEs.
Furthermore, a slight imbalance of acute renal failure, disfavouring selexipag, was observed. Renal and
urinary disorders reported as previous or concomitant diseases higher in the selexipag group (13.1%)
than in the placebo group (10.3%). However, it cannot fully be excluded that the prostacyclin-like
action of selexipag could worsen renal function because of the complex effects of prostaglandins on
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various organs. Thus, "renal function impairment" / "acute renal failure" have been listed as important
potential risks in the RMP.
Regarding SAEs, the total percentage of patients with at least one serious AE was numerically lower in
the selexipag than in the placebo group. This was mainly driven by the markedly lower incidence of
(worsening of) PAH in the selexipag group and was in line with the findings of the efficacy analysis. An
analysis of MACE events revealed an increase of them in the selexipag group. The imbalance in MACE
is essentially due to the imbalance in CV deaths because most of the MACE were fatal. Sudden death
and death due to heart failure were most frequent. MACE have been listed as important potential risks
in the RMP.
Until the end of treatment (EOT)+7 days, mortality was numerically higher in the selexipag group
compared to the placebo group (46 vs. 37 cases, HR 1.17). The imbalance was due to cardiovascular
death; non-CV death was fairly balanced between the groups. Notably, the difference between
selexipag and placebo was largest for deaths as part of the primary endpoint. This means that in the
selexipag group more often than in the placebo group death occurred without prior signs of PAH
worsening. This could indicate a merely symptomatic improvement by selexipag treatment without
affecting mortality. However, in their response the Applicant submitted a further analysis which also
included worsening of right heart function as a parameter for PAH progression as suggested in the
relevant CHMP guideline and with this analysis the number of deaths as first event decreased in the
selexipag group so that no relevant difference between selexipag and placebo remained (see efficacy
part of this report).
Analysis of mortality (as first event) is biased by informative censoring (see Efficacy and B/R part of
this report). Since presence of informative censoring does not rule out a true increase, a careful search
for mechanisms by which selexipag could potentially adversely affect mortality was performed. It was
observed that increased mortality with selexipag as compared to placebo was limited to patients with
FC II at baseline and with a cardiac index (CI) in the highest quartile. Cardiac index (CI) was found to
be significantly correlated with survival under selexipag treatment. Analyses suggested that selexipag
increases survival in low-CI patients but decreases survival in the high-CI patients, which is an
implausible biological and clinical finding. Furthermore, cross study comparisons suggested that the
mortality rate on selexipag in patients with FCII was not higher than expected, whereas the mortality
rate in FC II on placebo was remarkably low. No safety signal, overall or specifically related to FC II,
was detected and there is no clinical rationale why patients in functional class II with better cardiac
function should be more sensitive to a putative harmful effect of selexipag than patients in FC III/IV
with deteriorated cardiac function making a causal relationship between the observed increased
mortality and selexipag in the first event analysis is highly unlikely.The numerical increase in deaths
up to end of treatment + 7 days but not up to study closure was further investigated by mathematical
modelling, showing that the imbalance in deaths is consistent with the assumption of a neutral effect
on PAH mortality and reduction of non-fatal events (reference is made to section 3.4.5 Clinical
Efficacy).
Regarding vital signs, a transient and small increase in mean heart rate (HR; around 3 bpm vs. plc)
was noted after dosing of selexipag compared to placebo in the pivotal GRIPHON trial.
Correspondingly, higher percentages of patients had increases in HR >10, > 15 or > 20 bpm with
selexipag compared to placebo. Although changes in heart rate were generally modest and similar to
those seen with other medicinal products approved for PAH, HR increases could be relevant in
vulnerable patients. Therefore, patients at high risk of experiencing cardiovascular events have been
excluded from treatment by including the iloprost contraindications (e.g. severe coronary artery
disease, status post myocardial infarction, unstable angina) into the SmPC of selexipag.
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Malignancies were found to be numerically more frequent in the selexipag group of the GRIPHON trial
(11 vs. 4 patients, selexipag vs. placebo). The surplus in the selexipag group is mainly due to skin
tumours which did not occur at all in the placebo group. Phototoxicity of selexipag and its metabolite
ACT-333679 was observed in non-clinical in-vitro screening tests and could not be excluded in a
dedicated trial. However, the Applicant pointed out that no signs of phototoxicity were observed in the
patients suffering skin tumours and that the incidence observed in the selexipag group is well within
the expectations based on the frequency of these tumours in the general population. Thus, a chance
finding is likely as the absolute number of cases was low. Of note, light-dependent non-melanoma skin
malignancies are listed as important potential risks in the RMP.
From the safety database all the adverse reactions reported in clinical trials have been included in the
Summary of Product Characteristics.
2.6.2 Conclusions on clinical safety
The applicant has provided mathematical models and simulations that can explain the finding of a
numerically higher rate of deaths in the first overall event analysis as a result of informative censoring.
These show that the finding of an imbalance for death as first event up to EOT or EOT+7d is not
unexpected under the assumption that selexipag decreases non-fatal but not fatal events. For further
details see efficacy part of this report.
No specific/unique safety issue could be identified that could explain an increase in mortality with
selexipag. In addition, any putative safety issue leading to increased mortality would be more likely to
become evident in PAH patients with poor health condition as opposed to patients in FCII and better
cardiac functioning. Therefore, the observed increased mortality in the primary MM endpoint analysis
is most likely due to informative censoring and/or a chance finding and lacks biological or clinical
plausibility. Hence, CHMP considered the mortality issue as satisfactorily addressed.
The CHMP considered acceptable to further monitor the safety profile as mentioned in the RMP, in the
clinical use setting as a post authorisation study included in the RMP.
In reference to the safety profile it is also agreed with the implementation of risk minimisation
activities as proposed by the applicant and reflected into the Marketing Authorisation (see below for
details).
2.7 Risk Management Plan
The CHMP received the following PRAC Advice on the submitted Risk Management Plan:
The PRAC considered that the risk management plan version 4 is acceptable. In addition, minor
revisions were recommended to be taken into account before opinion. The PRAC endorsed PRAC
Rapporteur assessment report is attached.
The applicant implemented the changes in the RMP as requested by PRAC.
The CHMP endorsed the Risk Management Plan version 5 with the following content:
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Safety concerns
Important identified risks • Hypotension
•
Anaemia
Important potential risks • Pulmonary oedema associated with pulmonary veno-occlusive
disease
• Hyperthyroidism
• Major adverse cardiovascular events
• Renal function impairment / acute renal failure
• Bleeding events
• Light-dependent non-melanoma skin malignancies
• Ophthalmological effects associated with retinal vascular system
• Gastrointestinal disturbances denoting intestinal intussusception
(manifested as ileus or obstruction)
• Medication error
•
Off-label use
Missing information (or limited) • Use in paediatric patients
• Use in elderly over 75 years old
• Use during pregnancy and lactation
• Use in patients with severe hepatic impairment
• Use in patients undergoing dialysis
• Concomitant use with strong inhibitors of CYP2C8, UGT1A3 and
UGT2B7 or inducers of CYP2C8, UGT1A3, and UGT2B7
• Concomitant use with substrates of intestinal CYP3A4 and
CYP2C9
Pharmacovigilance plan
Study/activity
Type, title and
category (1-3)
Objectives
Safety concerns
addressed
Status
(planned,
started)
Date for
submission of
interim or final
reports (planned
or actual)
PASS:
observational
cohort study of
PAH patients
exposed and
unexposed to
Uptravi®
(selexipag) in
routine clinical
practice
Category 3
1. To describe
demographics, disease
characteristics and
clinical course in PAH
patients who either
initiated treatment with
Uptravi < 3 months
prior to or at enrolment
or during observation
(Uptravi exposed
patients), or were never
treated with Uptravi
(Uptravi unexposed
patients), overall and in
the subset of patients
> 75 years old
- Hypotension
- Anaemia / decreased
haemoglobin
concentration
- Pulmonary oedema
associated with
pulmonary veno-
occlusive disease
- Hyperthyroidism
- Major adverse
cardiovascular events,
i.e., PTs denoting
cardiovascular death,
sudden death, MI,
ischaemic or
hemorrhagic
Planned Final study report
2023
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Study/activity
Type, title and
category (1-3)
Objectives Safety concerns
addressed Status
(planned,
started)
Date for
submission of
interim or final
reports (planned
or actual)
2. To further characterise
the Uptravi safety
profile and estimate the
incidence rates during
the observation period
of all-cause death and
the important identified
or potential risks [see
list in column ‘Safety
concerns addressed’]
3. To compare rates of
MACE and all-cause
death between Uptravi
exposed patients and
Uptravi unexposed
patients, stratified using
a propensity score
analysis.
cerebrovascular
disorder
- Renal function
impairment / acute
renal failure
- Bleeding events
- Light-dependent non-
melanoma skin
malignancies
- Ophthalmological
effects associated with
retinal vascular system
- GI disturbances
denoting intestinal
intussusception
(manifested as ileus or
obstruction)
PASS to evaluate
medication error
risk minimisation
measures for the
Uptravi titration
phase
Category 3
To evaluate medication
error risk minimisation
measures during the Uptravi
titration phase.
To record the occurrence of
‘wrong dose’ medication
errors self-reported by the
patient.
Occurrence of medication
errors during the Uptravi
titration phase
Planned
Final study report
2020
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Risk minimisation measures
Important identified risks
Safety concern Routine risk minimisation measures Additional risk minimisation
measures
Hypotension Proposed SmPC
Hypotension is described in section 4.4:
‘Hypotension
Uptravi has vasodilatory properties that
may result in lowering of blood pressure.
Before prescribing Uptravi, physicians
should carefully consider whether
patients with certain underlying
conditions could be adversely affected by
vasodilatory effects (e.g., patients on
antihypertensive therapy or with resting
hypotension, hypovolaemia, severe left
ventricular outflow obstruction or
autonomic dysfunction).’
Hypotension is included in section 4.8
Undesirable effects in the ADR table as a
common adverse reaction.
Other routine risk minimisation
measures
None
None proposed
Anaemia Proposed SmPC
Anaemia and haemoglobin decreased are
included in section 4.8 Undesirable
effects in the ADR table as common
adverse events.
Changes in haemoglobin in PAH patients
in the GRIPHON study are included in
section 4.8 Undesirable effects under the
ADR table under Description of selected
adverse reactions:
‘Haemoglobin decrease
In a Phase 3 placebo-controlled study in
patients with PAH, mean absolute
changes in haemoglobin at regular visits
compared to baseline ranged from −0.34
to −0.02 g/dL in the selexipag group
compared to −0.05 to 0.25 g/dL in the
placebo group. A decrease from baseline
in haemoglobin concentration to below 10
g/dL was reported in 8.6% of selexipag-
treated patients and 5.0% of placebo-
treated patients.’
Other routine risk minimisation
measures
None proposed
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None
Important potential risks
Pulmonary oedema
associated with pulmonary
veno-occlusive disease
Proposed SmPC
PVOD is described in section 4.4:
‘Pulmonary veno-occlusive disease
Cases of pulmonary oedema have been
reported with vasodilators (mainly
prostacyclins) when used in patients with
pulmonary veno-occlusive disease.
Consequently, if signs of pulmonary
oedema occur when Uptravi is
administered in patients with PAH, the
possibility of pulmonary veno-occlusive
disease should be considered. If
confirmed, treatment with Uptravi should
be discontinued.’
Other routine risk minimisation
measures
None
None proposed
Hyperthyroidism Proposed SmPC
Hyperthyroidism is listed in section 4.4:
‘Hyperthyroidism
Hyperthyroidism has been observed with
Uptravi. Thyroid function tests are
recommended as clinically indicated in
the presence of signs or symptoms of
hyperthyroidism.’
Hyperthyroidism is included in section 4.8
Undesirable effects in the ADR table as a
common adverse event.
Values of thyroid function tests in the
GRIPHON study are included in section
4.8 Undesirable effects under the ADR
table:
‘Thyroid function tests
In a Phase 3 placebo-controlled study in
patients with PAH, hyperthyroidism was
reported for 1.6% of patients in the
selexipag group, compared to no case in
the placebo group (see section 4.4). A
reduction (up to −0.3 MU/L from a
baseline median of 2.5 MU/L) in median
thyroid-stimulating hormone was
observed at most visits in the selexipag
group. In the placebo group, little change
in median values was apparent. There
were no mean changes in
triiodothyronine or thyroxine in either
group.’
None proposed
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Other routine risk minimisation
measures
None
Major adverse
cardiovascular events
Proposed text in SmPC
Relevant contraindications listed in
section 4.3
‘• Severe coronary heart disease or
unstable angina.
• Myocardial infarction within the last
6 months.
• Decompensated cardiac failure if not
under close medical supervision.
• Severe arrhythmias.
• Cerebrovascular events (e.g.,
transient ischaemic attack, stroke) within
the last 3 months.
• Congenital or acquired valvular
defects with clinically relevant myocardial
function disorders not related to
pulmonary hypertension.’
Other routine risk minimisation
measures
None
None proposed
Renal function impairment
/ acute renal failure
None None proposed
Bleeding events
None
None proposed
Light-dependent non-
melanoma skin
malignancies
None None proposed
Ophthalmological effects
associated with retinal
vascular system
Proposed text in SmPC
Nonclinical data described in section 5.3:
‘Tortuosity of retinal arterioles was noted
after 2 years of treatment only in rats.
Mechanistically, the effect is considered
to be induced by life-long vasodilation
and subsequent changes in ocular
haemodynamics. Additional
histopathological findings of selexipag
were observed only at exposures
sufficiently in excess of the maximum
human exposure, indicating little
relevance to humans.’
Other routine risk minimisation
measures
None
None proposed
Gastrointestinal
disturbances denoting
intestinal intussusception
Proposed text in SmPC
Administration in paediatric population
not recommended in section 4.2:
None proposed
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(manifested as ileus or
obstruction)
‘Paediatric population (< 18 years)
The safety and efficacy of Uptravi in
children aged 0 to less than 18 years
have not yet been established. No data
are available. Administration of selexipag
in the paediatric population is not
recommended. Animal studies indicated
an increased risk of intussusception, but
the clinical relevance of these findings is
unknown (see section 5.3).’
Description of nonclinical data in section
5.3:
‘In juvenile dogs, intussusception due to
prostacyclin-related effects on intestinal
motility was observed sporadically.
Safety margins adapted for IP receptor
potency for the active metabolite were 2-
fold (based on total exposure) in relation
to human therapeutic exposure. The
finding did not occur in mouse or rat
toxicity studies. Because of the species-
specific sensitivity of dogs to develop
intussusception, this finding is considered
not relevant for adult humans.’
Other routine risk minimisation
measures
None
Medication error Proposed text in SmPC
Under section 4.2 Posology and method
of administration:
‘Treatment should only be initiated and
monitored by a physician experienced in
the treatment of PAH.’
Other routine risk minimisation
measures
Product information clear and
understandable to the HCP and
patients
Maximise easy identification and
maximum differentiation by choice of
colour of the two dosage strengths to
be used during the titration phase
(light yellow and green)
Packaging design of strengths used
during the titration process: the
non-transparent alu/alu foil of the
blister is maximally visually
differentiated, matching the colour of
the tablet and that used for the outer
carton
Controlled Access System
Educational material in a prescriber kit
containing:
Cover letter to the HCP and pharmacist
A4 laminated card HCP titration guide
SmPC
Package leaflet and patient titration guide
Patient titration guide included in the
titration pack
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Off-label use Proposed SmPC
Clear indication of target population is
detailed in the indication section 4.1 of
the SmPC:
‘Uptravi is indicated for the long-term
treatment of pulmonary arterial
hypertension (PAH) in adult patients with
WHO functional class (FC) II–III. Uptravi
may be used as combination therapy in
patients insufficiently controlled on
treatment with an endothelin receptor
antagonist (ERA) and/or a
phosphodiesterase type 5 (PDE-5)
inhibitor, or as monotherapy in patients
who are not candidates for these
therapies.
Efficacy has been shown in a PAH
population including idiopathic and
heritable PAH, PAH associated with
connective tissue disorders, and PAH
associated with corrected simple
congenital heart disease (see section
5.1).’
Other routine risk minimisation
measures
None
None proposed
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Missing information (or limited)
Use in paediatric patients Proposed SmPC
SmPC section 4.2:
‘Paediatric population (< 18 years)
The safety and efficacy of Uptravi in
children aged 0 to less than 18 years
have not yet been established. No data
are available. Administration of selexipag
in the paediatric population is not
recommended. Animal studies indicated
an increased risk of intussusception, but
the clinical relevance of these findings is
unknown (see section 5.3).’
Description of nonclinical data in section
5.3:
‘In juvenile dogs, intussusception due to
prostacyclin-related effects on intestinal
motility was observed sporadically.
Safety margins adapted for IP-receptor
potency for the active metabolite were 2-
fold (based on total exposure) in relation
to human therapeutic exposure. The
finding did not occur in mouse or rat
toxicity studies. Because of the
species-specific sensitivity of dogs to
develop intussusception, this finding is
considered not relevant for adult
humans.’
Other routine risk minimisation
measures
None
None proposed
Use in elderly over
75 years old
Proposed SmPC
Section 4.2:
‘Elderly (≥ 65 years)
No adjustment to the dosing regimen is
needed in elderly people (see section
5.2). There is limited clinical experience
in patients over the age of 75 years,
therefore Uptravi should be used with
caution in this population (see section
4.4).’
Caution in section 4.4:
‘Elderly (≥ 65 years)
There is limited clinical experience with
selexipag in patients over the age of 75
years, therefore Uptravi should be used
with caution in this population (see
section 4.2).’
Other routine risk minimisation
measures
None proposed
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None
Use during pregnancy and
lactation
Proposed SmPC
Section 4.4:
Women of childbearing potential
Women of childbearing potential should
practise effective contraception while
taking selexipag.
Section 4.6:
Women of childbearing potential /
Contraception in males and females
Women of childbearing potential should
practise effective contraception while
taking selexipag.
Pregnancy
There are no data from the use of
selexipag in pregnant women. Animal
studies do not indicate direct or indirect
harmful effects with respect to
reproductive toxicity. Selexipag and its
main metabolite showed 20- to 80-times
lower prostacyclin (IP) receptor potency
in vitro in animal species used in
reproductive toxicity testing compared to
humans. Therefore, safety margins for
potential IP receptor-mediated effects on
reproduction are accordingly lower than
for non-IP-related effects (see section
5.3).
Uptravi is not recommended during
pregnancy and in women of child-bearing
potential not using contraception.
Breast-feeding
It is unknown whether selexipag or its
metabolites are excreted in human milk.
In rats, selexipag or its metabolites are
excreted in milk (see section 5.3). A risk
to the suckling child cannot be excluded.
Uptravi should not be used during breast-
feeding.’
Other routine risk minimisation
measures
None
None proposed
Use in patients with severe
hepatic impairment
Proposed SmPC
Dosage recommendation in section 4.2:
‘Hepatic impairment
Uptravi should not be administered in
patients with severe liver impairment
(Child-Pugh class C; see section 4.4). For
patients with moderate hepatic
None proposed
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impairment (Child-Pugh class B), the
starting dose of Uptravi should be 200
micrograms once daily, and increased at
weekly intervals by increments of 200
micrograms given once dailyuntil adverse
reactions, reflecting the mode of action of
selexipag, that cannot be tolerated or
medically managed, are experienced. No
adjustment to the dosing regimen is
needed in patients with mild hepatic
impairment (Child-Pugh class A).’
Caution in section 4.4:
‘Patients with hepatic impairment
There is no clinical experience with
selexipag in patients with severe liver
impairment (Child-Pugh class C),
thereforeUptravi should not be
administered in these patients. The
exposure to selexipag and its active
metabolite is increased in subjects with
moderate hepatic impairment (Child-
Pugh class B; see section 5.2). In
patients with moderate hepatic
impairment, Uptravi should be dosed
once daily (see section 4.2).’
PK described in section 5.2:
‘Hepatic impairment
In subjects with mild (Child-Pugh class A)
or moderate (Child-Pugh class B) hepatic
impairment, exposure to selexipag was
2- and 4-fold higher, respectively, when
compared to healthy subjects. Exposure
to the active metabolite remained almost
unchanged in subjects with mild hepatic
impairment and was doubled in subjects
with moderate hepatic impairment. Only
two subjects with severe (Child-Pugh
class C) hepatic impairment were dosed
with selexipag. Exposure to selexipag and
its active metabolite in these two
subjects was similar to that in subjects
with moderate (Child-Pugh class B)
hepatic impairment.
Based on modelling and simulation data
from a study in subjects with hepatic
impairment, the exposure to selexipag at
steady state in subjects with moderate
hepatic impairment (Child-Pugh class B)
after a once-daily regimen is predicted to
be approximately 2-fold higher than that
in healthy subjects during a twice-daily
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regimen. The exposure to the active
metabolite at steady state in these
patients during a once-daily regimen is
predicted to be similar to that in healthy
subjects during a twice-daily regimen.
Subjects with severe hepatic impairment
(Child-Pugh class C) showed similar
predicted exposure at steady state as
subjects with moderate hepatic
impairment during a once-daily regimen.’
Other routine risk minimisation
measures
None
Use in patients undergoing
dialysis
Proposed SmPC
Dosage recommendation in section 4.2:
‘Renal impairment
No adjustment to the dosing regimen is
needed in patients with mild or moderate
renal impairment. No change in starting
dose is required in patients with severe
renal impairment (estimated glomerular
filtration rate [eGFR]
< 30 mL/min/1.73 m2); dose titration
should be done with caution in these
patients (see section 4.4).’
Caution in section 4.4:
‘Patients with renal impairment
In patients with severe renal impairment
(eGFR < 30 mL/min/1.73 m2) caution
should be exercised during dose titration.
There is no experience with Uptravi in
patients undergoing dialysis (see section
5.2), therefore Uptravi should not be
used in these patients.’
Other routine risk minimisation
measures
None
None proposed
Concomitant use with
strong inhibitors of
CYP2C8, UGT1A3 and
UGT2B7 or inducers of
CYP2C8, UGT1A3, and
UGT2B7
Proposed SmPC
Listed in section 4.5 under Effect of other
medicinal products on selexipag:
‘Inhibitors or inducers of CYP2C8,
UGT1A3, and UGT2B7
The effect of inhibitors of CYP2C8
(gemfibrozil), inhibitors of UGT1A3 and
UGT2B7 (valproic acid, probenecid, and
fluconazole), inducers of CYP2C8
(rifampicin, rifapentine), or inducers of
UGT1A3, and UGT2B7 (rifampicin) on the
exposure to selexipag and its active
metabolite has not been studied. Caution
None proposed
Uptravi (Selexipag) Assessment Report
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is required when administering these
medicinal products concomitantly with
Uptravi. A potential pharmacokinetic
interaction with strong inhibitors or
inducers of these enzymes cannot be
excluded.’
Other routine risk minimisation
measures
None
Concomitant use with
substrates of intestinal
CYP3A4 enzyme
Proposed SmPC
Listed in section 4.5 under Effect of
selexipag on other medicinal products:
‘Selexipag and its active metabolite do
not inhibit cytochrome P450 enzymes at
clinically relevant concentrations.
Selexipag and its active metabolite do
not inhibit transport proteins. Selexipag
and its active metabolite are not
expected to induce cytochrome P450
enzymes in the liver and kidney at
clinically relevant concentrations. In vitro
data indicate that selexipag could be an
inducer of both CYP3A4 and CYP2C9 in
the intestine.’
Other routine risk minimisation
measures
None
None proposed
2.8 Pharmacovigilance
Pharmacovigilance system
The CHMP considered that the pharmacovigilance system summary submitted by the applicant fulfils
the requirements of Article 8(3) of Directive 2001/83/EC.
2.9 Product information
2.9.1 User consultation
The results of the user consultation with target patient groups on the package leaflet submitted by the
applicant show that the package leaflet meets the criteria for readability as set out in the Guideline on
the readability of the label and package leaflet of medicinal products for human use.
2.9.2 Additional monitoring
Pursuant to Article 23(1) of Regulation No (EU) 726/2004, Uptravi (selexipag) is included in the
additional monitoring list as it contains a new active substance which, on 1 January 2011, was not
contained in any medicinal product authorised in the EU.
Therefore the summary of product characteristics and the package leaflet includes a statement that
Uptravi (Selexipag) Assessment Report
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this medicinal product is subject to additional monitoring and that this will allow quick identification of
new safety information. The statement is preceded by an inverted equilateral black triangle.
3. Benefit-Risk Balance
Benefits
The application is based on one pivotal clinical study (GRIPHON) which was an endpoint-driven trial
that investigated the effect of selexipag on morbidity and mortality with onset date up to 7 days after
last study drug intake in patients with PAH. The primary composite endpoint included the components
death (all causes), hospitalization for worsening of PAH based on predefined criteria, worsening of PAH
resulting in need for lung transplantation or balloon atrial septostomy, initiation of parenteral
prostanoid therapy or chronic oxygen therapy due to worsening of PAH and confirmed disease
progression. Disease progression was defined by a decrease in the 6 Minute Walk Test (MWT) by at
least 15% that is accompanied either by a) Worsening of NYHA/WHO Functional Class (FC) (patients in
FC II-III) or by b) Need for additional PAH-specific therapy (patients in FC III-(patients in FC III-IV).
Right heart failure, an endpoint component proposed in the relevant CHMP PAH guideline, was not part
of the composite endpoint. Median duration of double-blind study treatment was 70.7 weeks for the
selexipag and 63.7 weeks for the placebo group. After a primary morbidity/mortality event, patients
could enter an extension phase and either remain on selexipag, discontinue treatment or switch from
placebo to selexipag.
Beneficial effects
A statistically significant and clinically relevant benefit of selexipag vs. placebo has been demonstrated
for the composite primary morbidity and mortality endpoint (24.4% vs. 36.4%, 140 vs. 212 patients
with morbidity and mortality endpoint event. This beneficial effect was driven by a positive effect on
“disease progression” and “hospitalization due to PAH worsening”. There was no beneficial effect on all-
cause mortalityor quality of life.
A small beneficial effect was also observed for the 6 Minute Walk Test (-53 m vs. -66m). This effect
was more pronounced in patients with Functional Class III than in those with Functional Class II and in
treatment naïve patients comparedwas estimated to be larger [difference of +34 m vs. placebo at the
pre-defined timepoint of 6 months (99% CI: 10.0; 63.0, p = 0.0002)] than in patients pretreated with
ERA, PDEi or ERA+ PDEi (Point estimate and two-sided 99% CI for location shift, Hodges-Lehman
method -1 (-38.0; 28.0 m), +12.0 (-8.0; 33.0m), and +6.0 (-14.0; 24.0 m), respectively)]. In
patients with FC III/(IV) the difference was larger (+17.0 (-1.0; 36m) than in patients with FC (I)/II
(+5.0 (-8.0; 19.0 m)).
Overall, a benefit has been shown in adult patients with IPAH or PAH due to connective tissue disease,
in PAH associated with simple corrected congenital heart disease in WHO Functional Class II and III
either as combination therapy in patients insufficiently controlled with an endothelin receptor
antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor, or as monotherapy in patients
who are not candidates for these therapies. Maintenance of the effect has been sufficiently
demonstrated over time since it was a long-term endpoint-driven trial.
Selexipag will be the first orally available prostacyclin (PGI2) receptor agonist in the EU.
Uncertainty in the knowledge about the beneficial effects
The GRIPHON trial was not designed to investigate whether selexipag has disease modifying activity
with maintenance of an effect after cessation of therapy.
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Due to low numbers of patients in Functional Class I and IV included in GRIPHON study, efficacy in
these functional classes cannot be reliably assessed. Thus, these patients are not included in the
indication.
The individual components of the primary endpoint were assessed as secondary endpoints. Results
were all in favour of selexipag except for mortality, which was numerically increased with selexipag
compared to placebo (4.9% vs. 3.1%, 28 vs. 18 events at EOT+7 days follow up).
The observation of increased mortality in this analysis is prone to bias, and in consequence the event
rates above are potentially misleading, firstly the trial was event-driven and patient follow-up
contributing to the primary assessment of mortality ceased after their first primary outcome event,
which was usually a disease progression (morbidity) event. After a first morbidity event, patients were
allowed to cross over to another treatment: patients could remain on selexipag, discontinue treatment
or switch from placebo to selexipag. Experiencing a morbidity event was associated with a higher risk
of dying. Since more morbidity events occurred in the placebo group, more patients at high risk were
excluded from further follow-up in the placebo group than in the selexipag group with a consequence
that follow-up is shorter in the placebo group and follow-up from more patients that are at higher risk
is excluded from the placebo group, resulting in bias. Observation of the patient is ‘censored’ when
follow-up is discontinued according to the protocolled definition, and because the risk for those patients
is probably increased, the censoring is termed ‘informative’ for outcome (patients at increased risk are
more likely to be censored). In other words, due to the study design, the risk profile of the patients
changed during the course of the study, favouring placebo group at the end of the trial despite of
randomization. This is consistent with the observation that the imbalance did not emerge before month
18.
To explore the impact of these phenomena, mathematical simulations were conducted simulating the
trial design under scenarios assuming a beneficial effect of treatment on morbidity and a neutral effect
on mortality. These simulations indicated that, in a scenario where the placebo arm has increased
‘informative censoring’, there is a chance of at least a 70% to observe more deaths on selexipag and a
chance of 26% to 47% to observe a large difference of 9 or more deaths.
As stated above, the follow-up time on treatment was longer in the selexipag vs. the placebo group
(median 70.7 vs. 63.7 weeks, respectively. Adjustment for the difference in follow-up time (‘at risk
period’) reduces but does not remove the numerical difference in mortality: estimated mortality rate
(deaths per 100 patient years) is 5.45 in the selexipag and 4.64 in the placebo group, yielding a
hazard ratio (HR) of 1.17. However, this adjustment assumes a constant risk over time, whereas in
fact it can be understood that risks changed over time to a different degree in both arms.
The observed unfavourable effect on mortality as a primary endpoint event was less prominent when
signs and symptoms of right heart failure were also taken into account as proposed by the relevant
CHMP guideline on development of PAH medication (2.4% vs. 2.1%, 14 vs. 12 events, selexipag vs.
placebo, respectively). At study closure, mortality was comparable between treatment groups (100 vs.
105 cases for selexipag vs. placebo, respectively) but this comparison is hampered by the possibility of
open label cross-over to another treatment after the first morbidity event.
Of note, subgroup analyses for mortality indicated that the imbalance favouring placebo at EOT+7d
analysis was restricted to patients in Functional Class I/II (HR 1.7 [99% CI 0.59,4.91] and to patients
with cardiac index in the highest quartile as opposed to patients in Functional Class III/IV and patients
with low cardiac index. This is hence not suggestive of a true effect of selexipag on mortality due to
lack of biological or clinical plausibility. No safety issues were identified for selexipag that could explain
an increased mortality. (see safety section).
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Risks
Unfavourable effects
The safety information is mainly based on the double-blind, placebo-controlled treatment period of the
pivotal phase 3 study GRIPHON. The safety dataset of this study encompassed 1152 patients. Around
63% of patients were treated for at least one year.
Nearly all patients of the selexipag and of the placebo group had at least one AE during the double-
blind period of the GRIPHON study. There was a set of characteristic AEs which were markedly more
frequent with selexipag than with placebo. These AEs included various gastrointestinal (GI)
symptoms, pain at various locations and flushing. Furthermore, mean heart rate was increased after
administration of selexipag whereas mean systemic blood pressure was hardly affected; however,
events of hypotension were more frequent with selexipag than with placebo. All these events are in
line with the pharmacodynamic action of selexipag, i.e. activation of the IP receptor, and with the AE
profile of other prostacyclin (analogues). Beside these, a slight imbalance in anaemia, acute renal
failure and hyperthyroidism, both disfavouring selexipag, was observed.
Serious AEs (SAEs) during the double-blind treatment period were numerically lower in the selexipag
than in the placebo group (43.8% vs. 47.1%). The difference was mainly due to the lower incidence of
(worsening of) PAH in the selexipag group, which was in line with the findings of the efficacy analysis.
Within the SAE analysis, SAEs with fatal outcome were reported more frequently in the selexipag
than in the placebo group (8.5% vs. 7.1%). The imbalance was mainly due to increased reports of
PAH-related fatal events in the selexipag group (e.g. worsening of PAH, right ventricular failure or
cardiopulmonary failure); this reflects the mortality findings at EOT+7 days in the efficacy analysis.
Major Cardiovascular Events (MACE) were also increased in the selexipag group as compared to
placebo (7.1% vs. 5.7%, up to End of Treatment + 7 days). Most of the observed MACE were fatal;
sudden death and death due to heart failure were the most frequent categories.
Laboratory findings (vital signs) included an increased heart rate (HR) for about 3 hours after each
injection (i.e. twice daily). The increase was 5.4 bpm in the selexipag group vs. 2.1 bpm in the placebo
group. Correspondingly, the number of patients with transient HR increases >10, >15, or >20 bpm
was higher on selexipag than on placebo (10.5% vs. 3.1% for HR increase between >15 and 20 bpm,
5.9% vs. 2.3% for HR increase >20 bpm, selexipag vs. plc, measured 2h post-dose).
Uncertainty in the knowledge about the unfavourable effects
All-cause mortality was numerically higher in the selexipag group during the on-treatment period
(median 70.7 and 63.7 weeks for the selexipag and placebo group, respectively). The treatment
difference was largest for deaths that were considered as primary endpoint event (4.9% vs. 3.1%, Full
Analysis Set). Due to study design and endpoint definition, the mortality results are prone to bias. For
details see efficacy section above and discussion section below.
Only few patients aged 75 or above were present in the main safety database (GRIPHON study,
double-blind period). Therefore, safety information on this population is limited. Limited data are also
provided in patients with hepatic insufficiency.
Hypotension was more frequent with selexipag. Data on the influence of accompanying PAH medication
is not fully conclusive.
The significance of the observed imbalance in acute renal failure is not clear. Further investigation of
the individual cases did not suggest an underlying mechanism; however, a direct effect of selexipag on
the kidney via its prostacyclin-like mode of action cannot be excluded. Therefore, "renal function
impairment / acute renal failure" are listed in the RMP as important potential risks.
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Benefit-risk balance
Importance of favourable and unfavourable effects
There is a medical need for new medicinal products for the treatment of PAH, in particular in the add-
on treatment. Despite of available treatment options, PAH continues to be a life-threatening and
debilitating disease. Currently, only parenteral or inhaled prostacyclin (analogues) are available and
difficulties and undesired effects associated with their administration frequency and/or route of
administration are stated to result in under treatment (Lang IM, Eur Respir Rev 2015). Therefore, an
orally available prostacyclin (IP) receptor agonist such as selexipag would be a valuable addition
to the armamentarium of medicinal products for the treatment of PAH.
Selexipag was shown to provide a statistically significant and clinically relevant reduction of morbidity
events in patients with PAH. An improvement in survival has not been demonstrated. However, a
mortality benefit is not a requirement for approval and has not been demonstrated for any of the
approved specific PAH medications (except for i.v. epoprostenol in a small short-term study, Barst RJ,
New Eng J Med 1996). Cross study comparisons, although to be interpreted with caution due to
different patient populations, study designs, study durations and endpoints in most of these studies,
suggest that efficacy of selexipag may be somewhat lower than that of non-prostacyclin PAH-specific
medications. However, the treatment benefit of selexipag in itself as determined in GRIPHON is
statistically significant and clinically relevant.
The overall effect of selexipag on the 6MWD appears moderate. However, taking into consideration
the clinically relevant effect in treatment naive patients that was in the range of other medicinal
products approved for PAH and the well known observation that the effect on the 6 MWD is much less
pronounced in pretreated patients (about 80% of patients in GRIPHON were pretreated with one or two
PAH medications), the moderate mean overall effect on 6-MWD observed in the study is mainly related
to the high number of pretreated patients included in the study but does not indicate an overall lack of
efficacy.
Despite a clear effect on morbidity, no improvement in quality of life (QoL) could be shown for
selexipag compared to placebo. This lack of association is difficult to explain since even a merely
symptomatic effect would be expected to result in an improved QoL scale. Although the CAMPHOR
(Cambridge Pulmonary Hypertension Outcome Review) questionnaire used in GRIPHON has been
validated in mainly small populations with PAH in different regions, it is unclear at present whether it is
sensitive to changes in QoL. Therefore, the lack of impact of selexipag on QoL as measured by the
CAMPHOR questionnaire does not invalidate the beneficial effects on morbidity events.
The observed increased mortality as a primary endpoint event on selexipag compared to placebo was
the most serious concern raised during the review of this application and for the conclusion on benefit
risk. The observation is plausibly explained by differences in duration of exposure and (as
demonstrated in the simulations) by informative censoring. Based on statistical analyses and
simulations, analyses of the safety characteristics and supported by cross study comparisons, a true
negative effect on mortality was considered highly unlikely.
Indeed, even if the difference in mortality as first endpoint event would not be fully explained by
informative censoring, a detrimental effect of selexipag on mortality appears highly unlikely due the
following considerations: a) selexipag exerted a beneficial effect on morbidity events in patients with
PAH, which in turn were shown to be predictive for mortality events, b) selexipag is a prostacyclin
analogue with the typical adverse event profile of this known class of PAH medications; prostacyclins
are not suspected to be associated with an increased risk of mortality, c) the increase in heart rate
after each dose is generally modest and transient and in the range of other vasodilatory drugs
approved for PAH, d) There was no obvious explanation for the observed pattern that the imbalance
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was limited to patients with FC II and better cardiac functioning. These patients should be less
vulnerable to adverse effects than patients in FC III (and IV) and deteriorated cardiac function and
there was no other unfavourable pattern seen in FC II. In a cross study comparison, mortality rate on
selexipag in FC II was within the expected range, whereas the rate in the placebo arm was lower than
expected. E.g. patients with PAH included in the REVEAL Registry (Farber et al., Chest. 2015 Oct
1;148(4):1043-54) had an estimated 5-year survival rate of 88.0%, 75.6%, 57.0%, and 27.2% in FC
I, II, III, and IV, respectively, if they were diagnosed previously. For newly diagnosed patients, 5-year
survival rates were 72.2%, 71.7%, 60.0%, and 43.8%, respectively. The about 11% 3-year mortality
rate in FC II on selexipag in the GRIPHON study does not indicate an increased risk. The result on
selexipag fits better to these published survival rates than the < 4% 3-year mortality rate observed in
the placebo arm.
Taken together, the CHMP concluded that the observed increase in all cause mortality in the first event
analysis was most likely an artefact due to informative censoring and/or a chance finding.
Selexipag was generally well tolerated and exhibited the typical AE profile known for the class of
prostacyclin (analogues).
The transient and, on average, mild increase in heart rate after each administered dose of selexipag
is of similar magnitude as reported for other vasodilatory PAH medication. However, in some patients
the increase may be more pronounced and harmful, e.g. in patients at high risk for cardiovascular
events.
There was an imbalance in events of acute renal failure in the GRIPHON study (double-blind period),
disfavouring selexipag. Not all of these events were considered serious because they reflected a
transient decrease in renal function in patients with known chronic kidney disease. The number of
cases was small (14 vs. 7) so that a chance finding cannot be excluded. There is no clear mechanistic
link although prostacyclin (and thereby selexipag) may theoretically affect renal function, e.g. by
affecting renal perfusion. However, since the number of events was small and the imbalance of serious
events was less pronounced (10 vs. 7) the impact of this observation on B/R is considered low.
Hypotension was more frequent with selexipag, which can be explained by a systemic vasodilatory
effect of selexipag via the IP receptor. This finding is also in accordance with the observation of slightly
increased heart rate after each administration. The incidence of serious hypotension was low and was
balanced between the selexipag and the placebo group so that the impact on Benefit/Risk is considered
minimal. Mentioning in the SmPC is considered sufficient. A more pronounced imbalance (selexipag vs.
placebo) in hypotension was observed in patients receiving concomitant ERA and PDE5i. This is
mechanistically a plausible explanation however the number of patients and events in this subgroup
was too low for definite conclusions.
Benefit-risk balance
The B/R balance for selexipag in the proposed second-line indication is considered favourable.
Discussion on the benefit-risk balance
Selexipag clearly reduced morbidity events in patients with PAH, which is a clinically relevant benefit.
The beneficial effect on the 6-MWT in treatment naïve patients was within the range of other approved
medicinal products and is considered clinically meaningful. It is also expected to observe a less
pronounced effect in pretreated patients as observed with other treatments in PAH. Overall, the
efficacy of selexipag appears to be moderate mainly related to the high number (80%) of pretreated
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patients in the study and may potentially be lower than that of approved non-prostacyclin PAH
medications, which are usually considered as first-line treatments in PAH.
Selexipag is the first orally available prostacyclin (IP) receptor agonist with proven long-term efficacy,
compared to the currently approved prostacyclin analogues that have to be administered parenterally
or by inhalation and are associated with risks such as embolism and thrombosis (continuous i.v.
administration), local reactions (s.c. administration) or are time consuming (frequent inhalation).
Considering all analyses and arguments, the CHMP concluded that the finding of increased mortality in
the primary morbidity and mortality endpoint analysis is an artefact, which could be due to the study
design and explained by informative censoring and/or a chance finding.
Furthermore, no specific/unique safety issue could be identified that could explain the observed
increase in mortality in patients with FC II as opposed to more severe patients in FC III and FC IV,
thus providing additional reassurance that the observed increase in mortality is likely not attributable
to selexipag.
In view of the efficacy demonstrated together with an acceptable safety profile, the CHMP concluded
by majority on a positive benefit-risk balance. Selexipag is considered to provide a valuable orally
available treatment alternative for patients with PAH. Based on these considerations and since
selexipag was primarily assessed as an add-on treatment in the GRIPHON study, a second line
indication is considered appropriate as follows :
Uptravi is indicated for the long term treatment of pulmonary arterial hypertension (PAH) in adult
patients with WHO functional class (FC) II–III, either as combination therapy in patients insufficiently
controlled with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5)
inhibitor, or as monotherapy in patients who are not candidates for these therapies.
Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated
with connective tissue disorders, and PAH associated with corrected simple congenital heart disease
(see section 5.1).
Although there is no strong evidence from the trial data that the vasodilatory and heart rate effects of
selexipag are harmful for patients with a high risk of CV events, contraindications for approved
prostacyclin analogues (specifically iloprost) have been included in the product information of selexipag
as a precautionary measure.
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Table on Uptravi (selexipag)
Effe
cts
Description
Units
Selexipa
g
Placebo
Uncertainties/Limitations
Favourable Effects
Composite
endpoint
- Death (all causes) or
- Hospitalization for
worsening of PAH
based on predefined
criteria
- Worsening of PAH
resulting in need for
lung transplantation
or balloon atrial
Septostomy
- Initiation of
parenteral prostanoid
therapy or chronic
oxygen therapy due
to
worsening of PAH
- Disease progression:
Decrease in 6MWD
from Baseline and
a) Worsening of
NYHA/WHO FC
(patients in FC II-III)
b) Need for additional
PAH-specific therapy
(patients in FC III-
(patients in FC III-IV)
First
events/%
of
patients
a)
140/
24.4%
212/
36. 4%
Most components of the primary endpoint were in favour for
selexipag. The analysis of the single components was hampered by
informative censoring
(a) Analysis excluding events before Aug 16 2011
(selexipag vs. placebo:
Hospitalization for PAH worsening 12.4% vs. 16.5%, 71 vs. 96
events;
PAH worsening resulting in need for lung transplantation or balloon
atrial septostomy 0.2% vs. 0.3%, 1 vs. 2 events;
initiation of parenteral prostanoid therapy or chronic oxygen therapy
1.9% vs. 2.4%, 11 vs. 14 events; disease progression 5.6% vs.
14.4%, 32 vs. 84 events).
Only all-cause mortality was numerically in favour of placebo (on
treatment analysis: 4.4% vs. 2.7%, 25 vs. 16 events).
(b) Analysis including events before Aug 16 2011
(selexipag vs. placebo: Hospitalization for PAH worsening 13.6% vs.
18.7%, 78 vs. 109 events;
PAH worsening resulting in need for lung transplantation or balloon
atrial septostomy 0.2% vs. 0.3%, 1 vs. 2 events;
initiation of parenteral prostanoid therapy or chronic oxygen therapy
1.7% vs. 2.7%, 10 vs. 13 events; disease progression 6.6 vs.
17.2%, 38 vs. 100 events).
Only all-cause mortality was numerically in favour of placebo (on
treatment analysis: 4.9% vs. 3.1%, 28 vs. 18 events).
(b)
155/
27.0%
42/41.6%
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Effe
cts
Description
Units
Selexipa
g
Placebo
Uncertainties/Limitations
6-MWT
Median
Mean (SD)
No worsening
m
m
%
4.0
-53
(150.24)
77.8%
-9.0
-66
(148.23)
74.9%
PAH death
or PAH
hosp.
events
102
(17.8%)
137
(23.5%)
CAMPHOR
Quality of
life
Breathlessn
ess
subscore
scale
-1.0
0.0
0.0
0.0
Composite
endpoint as
proposed
by CHMP
guideline
- Death (all causes) or
- Hospitalization for
worsening of PAH
based on predefined
criteria
- Signs or symptoms
of right sided heart
failure
- Increase in WHO FC
from baseline -
Decrease in 6MWD
from Baseline by at
least 15%
First
events/%
of
patients
268/46.7
%
343/58.9
%
All components of the primary endpoint were in favour of selexipag
except for all-cause mortality, which was numerically slightly in
favour of placebo on treatment (2.4% vs. 2.1%, 14 vs. 12 events).
The analysis of the single components was hampered by informative
censoring.
Unfav
ourabl
TEAEs
Headache
Diarrhoea
Pain in Jaw
Nausea
%
65.2
42.4
25.7
33.6
32.8
19.1
6.2
18.5
Selexipag exhibited the typical AE profile of prostacyclin (analogues)
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Effe
cts
Description
Units
Selexipa
g
Placebo
Uncertainties/Limitations
Myalgia
Vomiting
Pain in extremity
Flushing
Arthralgia
Anaemia
Abdominal pain
Decreased appetite
Pain
Nasopharyngitis
Hypotension
Anaemia or decreased
haemoglobin
acute renal failure
renal impairment
hyperthyroidism
16.0
18.1
16.9
12.2
10.8
8.3
8.3
5.9
3.1
13.0
5.9
10.4
2.4
0.7
1.6
5.9
8.5
8.0
5.0
7.6
5.4
5.7
3.3
0.5
10.9
3.8
8.0
1.2
0
0
Renal toxicity is included as potential risk in the RMP
Death as a first event was possibly biased in favour of placebo due
to informed censoring
Interpretation of death up to study closure is hampered due to the
possibility of cross-over after the first morbidity event.
Malignancies
MACE
Death (first event up
to EOT + 7 days)
Patients
%
n (%)
11
2.4%
28
(4.9%)
4
1.4%
18 (3.1)
All deaths up to EOT
+ 7 days
Death due to PAH
All deaths up to study
closure
46 (8.0)
33 (71.7)
100
(17.4)
70 (12.2)
37 (6.4)
27 (73.0)
105
(18.0)
83 (14.3)
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4. Recommendations
Similarity with authorised orphan medicinal products
The CHMP by consensus is of the opinion that selexipag is not similar Volibris, Opsumit and Adempas
within the meaning of Article 3 of Commission Regulation (EC) No. 847/200.
Outcome
Based on the CHMP review of data on quality, safety and efficacy, the CHMP considers by majority
decision that the risk-benefit balance of Uptravi for the following indication: "long term treatment of
pulmonary arterial hypertension (PAH) in adult patients with WHO functional class (FC) II–III, either
as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist
(ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor, or as monotherapy in patients who are
not candidates for these therapies.
Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated
with connective tissue disorders, and PAH associated with corrected simple congenital heart disease
(see section 5.1)"
is favourable and therefore recommends the granting of the marketing authorisation subject to the
following conditions:
Conditions or restrictions regarding supply and use
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
Conditions and requirements of the Marketing Authorisation
• Periodic Safety Update Reports
The requirements for submission of periodic safety update reports for this medicinal product are set
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and any subsequent updates published on the European medicines web-portal.
Conditions or restrictions with regard to the safe and effective use of the medicinal product
• Risk Management Plan (RMP)
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent
updates of the RMP.
An updated RMP should be submitted:
• At the request of the European Medicines Agency;
• Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile or
as the result of an important (pharmacovigilance or risk minimisation) milestone being
reached.
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• Additional risk minimisation measures
Prior to launch of UPTRAVI in each Member State the Marketing Authorisation Holder (MAH) must
agree about the content and format of the Controlled Access System with the National Competent
Authority.
The Controlled Access System is aimed to facilitate the identification of prescribers, to approach them
with the appropriate information on the safe and effective use of UPTRAVI, and to provide them with
risk minimisation tools, especially regarding the potential risk of medication error. The Controlled
Access System should include three key principles that will be incorporated within each system in all
Member States. These are:
• The identification and maintenance of a list of all UPTRAVI prescribers
• The distribution of kits to all identified prescribers to minimise the risks of medication error in
particular
• Tracking of the receipt of the kits by prescribers
The MAH shall ensure that in each Member State where UPTRAVI is marketed, all healthcare
professionals who are expected to prescribe and/or dispense UPTRAVI are provided with a Prescriber
Kit containing the following:
• The Summary of Product Characteristics for UPTRAVI
• Cover letter to the HCP
• HCP A4 laminated titration guide
• Patient titration guide
The cover letter to the HCP should explain that the purpose of the educational materials is to reduce
the risk of medication error due to the availability of multiple tablets and dose strengths, and it should
provide a list of the content of the prescriber kit.
The HCP A4 laminated titration guide is intended to reduce the risk of medication error due to the
titration phase at treatment initiation with UPTRAVI and it should contain the following key elements:
• the dosing and titration concept
• the move to the maintenance dose (titration phase)
• expectations and management of adverse events during the titration phase
• encouragement and guidance for HCP to communicate clearly with the patient during their first
visit, as well as to take responsibility to contact the patient during the titration phase,
facilitating communication between HCP and the patient (need for contact and to schedule
telephone calls)
The Patient titration guide to be used by the HCP during discussions with the patient should contain the
following key elements:
• lay language version of the HCP A4 laminated titration guide
• diary to facilitate UPTRAVI use and serve as a reminder for the patients (e.g., to contact
her/his doctor), and a place to record intake of tablets
• information about the safe and effective use of UPTRAVI in lay language
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The patient titration guide along with the Patient Information Leaflet should be given to the patient
after the demonstration.
• Obligation to complete post-authorisation measures
Not applicable
Conditions or restrictions with regard to the safe and effective use of the medicinal product
to be implemented by the Member States.
Not applicable
New Active Substance Status
Based on the CHMP review of data on the quality properties of the active substance, the CHMP
considers that selexipag is qualified as a new active substance.
Divergent position(s) to the majority recommendation are appended to this report.
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APPENDIX 1
DIVERGENT POSITION DATED 1 April 2016 Rev 1
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The undersigned members of the CHMP did not agree with the CHMP’s positive opinion recommending
the granting of the marketing authorisation of Uptravi indicated for the long term treatment of
pulmonary arterial hypertension (PAH) in adult patients with WHO functional class (FC) II–III, either as
combination therapy in patients insufficiently controlled with an endothelin receptor antagonist (ERA)
and/or a phosphodiesterase type 5 (PDE-5) inhibitor, or as monotherapy in patients who are not
candidates for these therapies.
Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated
with connective tissue disorders, and PAH associated with corrected simple congenital heart disease
(see section 5.1).
The overall benefit-risk balance for Uptravi in the claimed indication is considered negative due to:
• A detrimental effect on mortality and major adverse cardiac events (MACE) and transient
ischemic attack (TIA) in the long-term cannot be ruled out.
• An increase in all-cause death with selexipag cannot be excluded (selexipag 46 events vs.
placebo 37 events; HR: 1.17; 95%CI: 0.66 to 2.07) and an increase in CV death cannot be
excluded (selexipag 38 events vs. placebo 29 events; HR: 1.24; 95%CI: 0.77 to 2.02) [Full
analysis set (FAS) up to End of Treatment plus seven days (EoT+7d). An increase in CV
mortality in the patients with a better prognostic at baseline (FCII, preserved cardiac index)
cannot be excluded (selexipag 15 events vs. placebo 6 events; HR: 2.24; 95%CI: 0.87 to
5.77) (FAS, EoT+7d). In addition, there were 7 cases of blindly adjudicated sudden cardiac
death (6 selexipag vs. 1 placebo) not related to PAH, in which a causal relationship with
selexipag cannot be ruled out (FAS, EOT+7d). Statistical artifacts, like informative censoring
cannot fully explain the imbalances observed in mortality.
• The same trend was noticed for the combination of fatal and non fatal MACE+TIA, for which an
increase be excluded (selexipag 43 events vs. placebo 33 events; HR: 1.24; 95%CI: 0.79 to
1.96) (FAS, EoT+7d).
• In the context of a disease with several specific medications available of different
pharmacological classes, including other prostacyclin agonists, the approval of a drug with such
uncertainties in CV safety and mortality is not endorsed.
Overall, for these reasons, I consider that the benefit/risk ratio is negative for Uptravi in the above
claimed indication.
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DIVERGENT POSITION
Uptravi EMEA/H/C/003774/0000
………………………………………….. …………………………………… …………………………...
Andrea Laslop Fatima Ventura Concepcion Prieto Yerro
…………………………………………. ……………………………………… ……………………………….
Daniela Melchiorri Karsten Bruins Slot Pieter De Graeff
…………………………………
Sol Ruiz
